Drug Delivery Medical Device

ABSTRACT

Provided is a coated implantable medical device, comprising: a substrate; and a coating disposed on the substrate, wherein the coating comprises at least one polymer and at least one pharmaceutical agent in a therapeutically desirable morphology and/or at least one active biological agent and optionally, one or more pharmaceutical carrying agents; wherein substantially all of pharmaceutical agent and/or active biological agent remains within the coating and on the substrate until the implantable device is deployed at an intervention site inside the body of a subject and wherein upon deployment of the medical device in the body of the subject a portion of the pharmaceutical agent and/or active biological agent is delivered at the intervention site along with at least a portion of the polymer and/or a at least a portion of the pharmaceutical carrying agents.

CROSS-REFERENCE

The present application is a continuation of U.S. patent applicationSer. No. 16/704,024, filed on Dec. 5, 2019 which is a divisional of U.S.patent application Ser. No. 13/809,324, filed on Feb. 26, 2013, which isa national phase entry under 35 U.S.C. § 371 of InternationalApplication No. PCT/US2011/044263, filed on Jul. 15, 2011, published inEnglish, which claims the benefit of U.S. Provisional Application No.61/428,785, filed on Dec. 30, 2010 and claims the benefit U.S.Provisional Application of 61/365,282 filed Jul. 16, 2010, thedisclosures of which are incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

There is a need for medical device technology that can rapidly,efficiently, reproducibly and safely transfer a Drug DeliveryFormulation from the surface of a percutaneous medical device (acoating) onto/into a specific site in the body.

SUMMARY OF THE INVENTION

Provided herein is a medical device comprising: a balloon; and a coatingon at least a portion of the balloon, wherein the coating comprises anactive agent and a binding agent, and wherein the device releases atleast 3% of the active agent to artery upon inflation of the balloon invivo.

Provided herein is a method of forming coating on a medical devicecomprising depositing a polymer on the medical device using an RESSprocess, and depositing an active agent and a binding agent on themedical device wherein depositing the active agent and the binding agentuses an eSTAT process.

Provided herein is a method comprising providing a device comprising aballoon and a coating on at least a portion of the balloon, wherein thecoating comprises an active agent and a binding agent; and inflating theballoon of the device in an artery in vivo, wherein upon inflating theballoon at least 3% of the active agent is transferred to tissue of theartery.

In some embodiments, the device releases at least 5% of the active agentto artery in vivo. In some embodiments, the device releases at least 10%of the active agent in vivo. In some embodiments, the device releases atleast 5% of the active agent to artery upon inflation of the balloon invivo. In some embodiments, the device releases at least 7% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 10% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases at least 15% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 20% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least25% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases at least 30% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 40% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases at least 50% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases between 2%> and 50% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 50% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between5%> and 50%> of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3%> and 30%>of the active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3%> and 25%> of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3%> and 20%> of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3%> and 15%> of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1%> and 15%) of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1%> and 10%> of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3%> and 10%> of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1%> and 5%> of the active agentto artery upon inflation of the balloon in vivo.

As used herein, depending on the embodiment, “upon inflation” means assoon as reasonably possible following removal of the device from thetreatment site. This may include timings such as about 1 minute, about 5minutes from removal of the device from the treatment site, within 1 to15 minutes from the removal of the device from the treatment site,within 1 to 15 minutes from the removal of the device from the treatmentsite, within 1 to 20 minutes from the removal of the device from thetreatment site, within 1 minute to 1 hour from the removal of the devicefrom the treatment site, within 1 minute to 2 hour from the removal ofthe device from the treatment site, and/or within 1 minute to 3 hoursfrom the removal of the device from the treatment site.

In some embodiments, the method comprises forming a dry mixture of theactive agent and the binding agent prior to depositing the active agentand the binding agent on the device. Forming the dry mixture compriseslyophilizing the active agent and binding agent.

In some embodiments of the methods and/or devices provided herein, theactive agent comprises a pharmaceutical agent.

The active agent in some embodiments of the devices, coatings and/ormethods provided herein comprises a macrolide immunosuppressive drug. Insome embodiments the macrolide immunosuppressive drug comprises one ormore of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1-yl)-rapamycin40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 40-O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicadoethoxy-2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus). The active agent may be selected from a macro lideimmunosuppressive drug, a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative and an analog thereof. The active agent may beselected from sirolimus, a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative and an analog thereof.

In some embodiments of the methods, coatings, and/or devices providedherein, the size of the active agent in the coating is controlled. Insome embodiments, the active agent is sirolimus and wherein thesirolimus has an average size (mean diameter) of at least one of: 1.5μητ, 2.5 μιη, 645 nm, 100-200 nm, another controlled size, or acombination thereof. In some embodiments, the active agent is sirolimusand wherein the sirolimus has a median size of at least one of: 1.5 μηι,2.5 μιη, 645 nm, 100-200 nm, another controlled size, or a combinationthereof. In some embodiments, the active agent is sirolimus and whereinthe sirolimus has an average size (mean diameter) of at least one of:about 1.5 μηι, about 2.5 μιη, about 645 nm, about 100-200 nm, anothercontrolled size, or a combination thereof. In some embodiments, theactive agent is sirolimus and wherein the sirolimus has a median size ofat least one of: about 1.5 μηι, about 2.5 μιη, about 645 nm, about100-200 nm, another controlled size, or a combination thereof. In someembodiments, the active agent is sirolimus and wherein sirolimus atleast 75% of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm,or another controlled size. In some embodiments, the active agent issirolimus and wherein sirolimus at least 50%> of the sirolimus as is 1.5μιη, 2.5 μιη, 645 nm, 100-200 nm, or another controlled size. In someembodiments, the active agent is sirolimus and wherein sirolimus atleast 90%> of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm,or another controlled size.

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 50% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 75% crystalline.

In some embodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 90% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 95% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein pharmaceutical agent is at least 98% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 99% crystalline.

In some embodiments of the devices, coatings and/or methods providedherein the polymer comprises PLGA. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises about 50:50Lactic acid:Glycolic acid. The PLGA may have at least one of: a MW ofabout 30 KDa and a Mn of about 15 KDa, a Mn of about 10 KDa to about 25KDa, and a MW of about 15 KDa to about 40 KDa.

In some embodiments of the devices, coatings and/or methods providedherein the coating comprises a positive surface charge on a surface ofthe coating configured to contact the treatment site.

In some embodiments of the devices, coatings and/or methods providedherein the coating comprises a binding agent. In some embodiments, thebinding agents comprises at least one of: Polyarginine, Polyarginine9-L-pArg, DEAE-Dextran (Diethylaminoethyl cellulose-Dextran), DMAB(Didodecyldimethylammonium bromide), PEI (Polyethyleneimine), TAB(Tetradodecylammonium bromide), and DMTAB (Dimethylditetradecylammoniumbromide). In some embodiments, the binding agent comprises a surfactant.In some embodiments the surfactant is cationic. In some embodiments thesurfactant comprises at least one of a primary amine having pH<10, and asecondary amine having pH<4. In some embodiments surfactant comprisesoctenidine dihydrochloride. In some embodiments the surfactant comprisesa permanently charged quaternary ammonium cation. In some embodimentsthe permanently charged quaternary ammonium cation comprises at leastone of: an Alkyltrimethylammonium salt such as cetyl trimethylammoniumbromide (CTAB), hexadecyl trimethyl ammonium bromide, cetyltrimethylammonium chloride (CTAC); Cetylpyridinium chloride (CPC);Polyethoxylated tallow amine (POEA); Benzalkonium chloride (BAC);Benzethonium chloride (BZT); 5-Bromo-5-nitro-1,3-dioxane;Dimethyldioctadecylammonium chloride; and Dioctadecyldimethylammoniumbromide (DODAB). In some embodiments the surfactant comprises at leastone of: didodecyldimethylammonium bromide (DMAB), linear isoformPolyethylenimine (linear PEI), Branched Low MW Polyethylenimine (PEI)(of about <25 KDa).

Branched Low MW

Polyethylenimine (PEI) (of about <15 KDa), Branched Low MWPolyethylenimine (PEI) (of about <10 KDa), Branched High MWPolyethylenimine (of about >/=25 KDa), Poly-L-Arginine (average ornominal MW of about 70,000 Da), Poly-L-Arginine (average or nominalMW>about 50,000 Da), Poly-L-Arginine (average or nominal MW of about5,000 to about 15,000 Da), Poly-L-Lysine (average or nominal MW of about28,200 Da), Poly-L-Lysine (average or nominal MW of about 67,000 Da),Poly Histidine, Ethylhexadecyldimethylammonium Bromide, DodecyltrimethylAmmonium Bromide, Tetradodecylammonium bromide, DimethylditetradecylAmmonium bromide, Tetrabutylammonium iodide, DEAE—Dextran hydrochloride,and Hexadimethrine Bromide. In some embodiments, the molecular weight ofthe binding agent is controlled. In some embodiments, the average sizeof the binding agent is controlled.

In some embodiments of the devices, coatings and/or methods providedherein the binding agent and the active agent are mixed and depositedtogether on the device. In some embodiments, the active agent andbinding agent are lyophilized prior to deposition on the device. In someembodiments dry particles of the active agent and binding agent aregenerated in another manner familiar to one of skill in the art and thencoated on the balloon or other medical device as described herein, suchas by an eSTAT coating process.

In some embodiments of the devices, coatings and/or methods providedherein the surfactant is deposited on a balloon after the active agentis deposited thereon.

The positive surface charge may be about 20 mV to about 40 mV. Thepositive surface charge may be at least one of: at least about 1 mV,over about 1 mV, at least about 5 mV, at least about 10 mV, about 10 mVto about 50 mV, about 20 mV to about 50 mV, about 10 mV to about 40 mV,about 30 mV to about 40 mV, about 20 mV to about 30 mV, and about 25 mVto about 35 mV.

In some embodiments of the methods, coatings, or devices providedherein, the ratio of the active agent to the binding agent is 1:1, 1:2,1:3, 1:4, 1:5, 1:10, 1:20, 2:1, 3:1, 4:1, 5:1, 10:1, 15:1, 20:1, 3:2,2:3, 5:2, 5:3, 2:5, 3:5, or another controlled ratio.

In some embodiments of the methods, coatings, or devices providedherein, the coating may comprise nanoparticles, and the nanoparticlesmay comprise an active agent and a polymer.

In some embodiments of the methods, coatings, or devices providedherein, the coating comprised and a 10:1 ratio of the active agent tothe binding agent, wherein the active agent comprises sirolimus whereinthe binding agent comprises Polyarginine. In some embodiments, thesirolimus has an average size of 1.5 μιη or 2.5 μιη. In someembodiments, the Polyarginine average molecular weight is 70 kDa. Insome embodiments, the Polyarginine average molecular weight is 5-15 kDa.In some embodiments, the active agent and the binding agent aredeposited on the balloon together using an eSTAT coating process. Insome embodiments, the active agent and the binding agent are lyophilizedprior to deposition on the balloon. In some embodiments, at least about2 ng/mg of active agent are found in arterial tissue 72 hours afterinflation of the balloon in the artery. In some embodiments, at leastabout 3 ng/mg of active agent are found in arterial tissue 72 hoursafter inflation of the balloon in the artery. In some embodiments, atleast about 5 ng/mg of active agent ae found in arterial tissue 72 hoursafter inflation of the balloon in the artery. In some embodiments, atleast about 10 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 20 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 30 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 40 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery.

In some embodiments of the methods, coatings, or devices providedherein, in vivo measurement comprises inflating the balloon inside theartery of a porcine for about 1 minute and wherein the amount of activeagent transferred to the artery is measured by UV-Vis evaluation of thecoating remaining on the balloon as determined about five minutes afterinflation of the balloon in the artery. In some embodiments of themethods, coatings, or devices provided herein, in vivo measurementcomprises inflating the balloon inside the artery of a porcine for about1 minute and wherein the amount of active agent transferred to theartery is measured by extracting the artery about five minutes afterinflation of the balloon in the artery and determining the amount ofdrug in the extracted artery using standard methods described hereinand/or known to one of skill in the art. In some embodiments of themethods, coatings, or devices provided herein, in vivo measurementcomprises inflating the balloon inside the artery of a rabbit for about1 minute and wherein the amount of active agent transferred to theartery is measured by UV-Vis evaluation of the coating remaining on theballoon as determined about five minutes after inflation of the balloonin the artery. In some embodiments of the methods, coatings, or devicesprovided herein, in vivo measurement comprises inflating the ballooninside the artery of a rabbit for about 1 minute and wherein the amountof active agent transferred to the artery is measured by extracting theartery about five minutes after inflation of the balloon in the arteryand determining the amount of drug in the extracted artery usingstandard methods described herein and/or known to one of skill in theart.

Provided herein is a method of forming a coating on a medical devicecomprising depositing a polymer on the medical device using an RESSprocess, mixing a binding agent and active agent to create an activeagent-binding agent mixture, lyophilizing the active agent-binding agentmixture and depositing the active agent-binding agent mixture on themedical device using an eSTAT process. In some embodiments, the bindingagent comprises a surfactant.

The coating may release the active agent into a treatment site over atleast one of: about 3 days, about 5 days, about 1 week, about 1.5 weeks,about 2 weeks, about 14 days, about 3 weeks, about 21 days, about 4weeks, about 28 days, about 1 month, about 1.5 months, about 2 months,at least about 3 days, at least about 5 days, at least about 1 week, atleast about 1.5 weeks, at least about 2 weeks, at least about 14 days,at least about 3 weeks, at least about 21 days, at least about 4 weeks,at least about 28 days, at least about 1 month, at least about 1.5months, at least about 2 months, about 7 to about 14 days, about 14 toabout 21 days, about 14 to about 28 days, about 21 to about 28 days, andabout 7 to about 28 days.

Provided herein is a coated medical device comprising: a medical devicefor delivering encapsulated active agent to a treatment site; and acoating on the medical device comprising the encapsulated active agentwherein the encapsulated active agent comprise active agent encapsulatedin a polymer, and wherein the encapsulated active agent has a positivesurface charge.

Provided herein is a coated medical device comprising: a medical devicefor delivering encapsulated active agent to a treatment site; and acoating on the medical device comprising the encapsulated active agentwherein the encapsulated active agent comprise a polymer that encapsulesat least a portion of an active agent, and wherein the encapsulatedactive agent has a positive surface charge.

In some embodiments, the active agent is not completely encapsulated. Anactive agent (or a portion thereof) need not be completely surrounded inorder to be encapsulated by the polymer. In some embodiments, at least10% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 20%> of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 25% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 30%> of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 40%> of the surface area of the active agent is encapsulated inthe polymer. In some embodiments, at least 50%> of the surface area ofthe active agent is encapsulated in the polymer. In some embodiments, atleast 60%> of the surface area of the active agent is encapsulated inthe polymer. In some embodiments, at least 70% of the surface area ofthe active agent is encapsulated in the polymer. In some embodiments, atleast 75% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 80%> of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 90%> of the surface area of the active agent is encapsulated inthe polymer. In some embodiments, at least 95% of the surface area ofthe active agent is encapsulated in the polymer. In some embodiments, atleast one of: at least 5%> of the surface area of the active agent is atleast partially surrounded by the polymer, at least 10%) of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 15% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 20% of the surfacearea of the active a{circumflex over ( )} *ent is at least partiallysurrounded by the polymer, at least 25% of the surface area of theactive a{circumflex over ( )} *ent is at least partially surrounded bythe polymer, at least 30% of the surface area of the active a{circumflexover ( )} *ent is at least partially surrounded by the polymer, at least40% of the surface area of the active a{circumflex over ( )} *ent is atleast partially surrounded by the polymer, at least 50% of the surfacearea of the active a{circumflex over ( )} *ent is at least partiallysurrounded by the polymer₃ at least 60% of the surface area of theactive a{circumflex over ( )} *ent is at least partially surrounded bythe polymer, at least 70% of the surface area of the active a{circumflexover ( )} *ent is at least partially surrounded by the polymer₃ at least75% of the surface area of the active a{circumflex over ( )} *ent is atleast partially surrounded by the polymer₃ at least 80% of the surfacearea of the active a{circumflex over ( )} *ent is at least partiallysurrounded by the polymer, at least 90% of the surface area of theactive a{circumflex over ( )} *ent is at least partially surrounded bythe polymer, and at least 95% of the surface area of the activea{circumflex over ( )} *ent is at least partially surrounded by thepolymer.

Provided herein is a coating for a medical device comprisingencapsulated active agent comprising active agent encapsulated in apolymer, wherein the encapsulated active agent has a positive surfacecharge, and wherein the coating delivers active agent to a treatmentsite over at least about 1 day.

Provided herein is a method of forming a coating on a medical devicecomprising providing encapsulated active agent comprising a polymer andactive agent, wherein the encapsulated active agent have a positivesurface charge, depositing the encapsulated active agent on the medicaldevice. In some embodiments, the coating delivers the active agent tothe treatment site over at least about 1 day.

Provided herein is a method of forming a coating on a medical devicecomprising providing encapsulated active agent comprising a polymer atleast partially encapsulating at least a portion of an active agentwherein the encapsulated active agent has a positive surface charge, anddepositing the encapsulated active agent on the medical device. In someembodiments, the coating delivers the active agent to the treatment siteover at least about 1 day.

In some embodiments, the active agent is not completely encapsulated. Anactive agent (or a portion thereof) need not be completely surrounded inorder to be encapsulated by the polymer. In some embodiments, at least10% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 20%> of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 25% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 30% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 40% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 50% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 60% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 70% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 75% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 80% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 90% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 95% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast one of: at least 5% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 10%) of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 15% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 20% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 25% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 30% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 40% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 50% of the surfacearea of the active agent is at least partially surrounded by thepolymer₃ at least 60% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 70% of the surfacearea of the active agent is at least partially surrounded by thepolymer₃ at least 75% of the surface area of the active agent is atleast partially surrounded by the polymer₃ at least 80% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 90% of the surface area of the active agent is atleast partially surrounded by the polymer, and at least 95% of thesurface area of the active agent is at least partially surrounded by thepolymer.

Provided herein is a coated medical device comprising: a medical devicefor delivering an active agent to a treatment site; and a coating on thedevice comprising the active agent, wherein the coated medical devicedelivers at least a portion of the coating to the treatment site whichportion releases active agent into the treatment site over at leastabout 1 day.

Provided herein is a coating for a medical device comprising an activeagent, wherein the coating delivers the into a treatment site over atleast about 1 day.

Provided herein is a method of forming coating on a medical device withof an active agent comprising depositing the active agent on the medicaldevice using an eSTAT process.

In some embodiments of the devices, coatings and/or methods providedherein the polymer comprises PLGA. The PLGA may have at least one of: aMW of about 30 KDa and a Mn of about 15 KDa, a Mn of about 10 KDa toabout 25 KDa, and a MW of about 15 KDa to about 40 KDa.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a bioabsorbable polymer. In some embodiments, theactive agent comprises a bioabsorbable polymer. In some embodiments, thebioabsorbable polymer comprises at least one of: Polylactides (PLA);PLGA (poly(lactide-co-glycolide)); Polyanhydrides: Polyorthoesters;Poly(N-(2-hydroxypropyl) methacrylamide); DLPLA—poly(dl-lactide);LPLA—poly(1-lactide); PGA—polyglycolide; PDO—poly(dioxanone);PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide);PGA-DLPLA-—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(I-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations, copolymers, and derivatives thereof. In some embodiments,the bioabsorbable polymer comprises between 1% and 95% glycolic acidcontent PLGA-based polymer.

In some embodiments of the methods and/or devices provided herein, thepolymer comprises at least one of polycarboxylic acids, cellulosicpolymers, proteins, polypeptides, polyvinylpyrrolidone, maleic anhydridepolymers, polyamides, polyvinyl alcohols, polyethylene oxides,glycosaminoglycans, polysaccharides, polyesters, aliphatic polyesters,polyurethanes, polystyrenes, copolymers, silicones, silicone containingpolymers, polyalkyl siloxanes, polyorthoesters, polyanhydrides,copolymers of vinyl monomers, polycarbonates, polyethylenes,polypropytenes, polylactic acids, polylactides, polyglycolic acids,polyglycohdes, polylactide-co-glycolides, polycaprolactones,poly(e-caprolactone)s, polyhydroxybutyrate valerates, polyacrylamides,polyethers, polyurethane dispersions, polyacrylates, acrylic latexdispersions, polyacrylic acid, polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, aliphatic polycarbonatespolyhydroxyalkanoates, polytetrahalooalkylenes, poly(phosphasones),polytetrahalooalkylenes, poly(phosphasones), and mixtures, combinations,and copolymers thereof. The polymers of the present invention may benatural or synthetic in origin, including gelatin, chitosan, dextrin,cyclodextrin, Poly(urethanes), Poly(siloxanes) or silicones,Poly(acrylates) such as [rho]oly(methyl methacrylate), poly(butylmethacrylate), and Poly(2-hydroxy ethyl methacrylate), Poly(vinylalcohol) Poly(olefins) such as poly(ethylene), [rho]oly(isoprene),halogenated polymers such as Poly(tetrafluoroethylene)—and derivativesand copolymers such as those commonly sold as Teflon® products,Poly(vinylidine fluoride), Poly(vinyl acetate), Poly(vinyl pyrrolidone),Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate),Poly(ethylene glycol), Poly(propylene glycol), Poly(methacrylic acid):etc. Suitable polymers also include absorbable and/or resorbablepolymers including the following, combinations, copolymers andderivatives of the following: Polylactides (PLA), Polyglycolides (PGA),PolyLactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl) methacrylamide), Poly(1-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(l-lactide);PDO—poly(dioxanone); PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide):PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

In some embodiments of the methods and/or devices provided herein, thepolymer has a dry modulus between 3,000 and 12,000 KPa. In someembodiments, the polymer is capable of becoming soft after implantation.In some embodiments, the polymer is capable of becoming soft afterimplantation by hydration, degradation or by a combination of hydrationand degradation. In some embodiments, the polymer is adapted totransfer, free, and/or dissociate from the substrate when at theintervention site due to hydrolysis of the polymer.

In some embodiments of the methods and/or devices provided herein, thebioabsorbable polymer is capable of resorbtion in at least one of: about1 day, about 3 days, about 5 days, about 7 days, about 14 days, about 3weeks, about 4 weeks, about 45 days, about 60 days, about 90 days, about180 days, about 6 months, about 9 months, about 1 year, about 1 to about2 days, about 1 to about 5 days, about 1 to about 2 weeks, about 2 toabout 4 weeks, about 45 to about 60 days, about 45 to about 90 days,about 30 to about 90 days, about 60 to about 90 days, about 90 to about180 days, about 60 to about 180 days, about 180 to about 365 days, about6 months to about 9 months, about 9 months to about 12 months, about 9months to about 15 months, and about 1 year to about 2 years.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a microstructure. In some embodiments, particles ofthe active agent are sequestered or encapsulated within themicrostructure. In some embodiments, the microstructure comprisesmicrochannels, micropores and/or microcavities. In some embodiments, themicrostructure is selected to allow sustained release of the activeagent. In some embodiments, the microstructure is selected to allowcontrolled release of the active agent.

In some embodiments of the devices, coatings and/or methods providedherein the coating comprises a positive surface charge. The positivesurface charge may be about 20 mV to about 40 mV. The positive surfacecharge may be at least one of: at least about 1 mV, over about 1 mV, atleast about 5 mV, at least about 10 mV, about 10 mV to about 50 mV,about 20 mV to about 50 mV, about 10 mV to about 40 mV, about 30 mV toabout 40 mV, about 20 mV to about 30 mV, and about 25 mV to about 35 mV.

In some embodiments of the devices, coatings and/or methods providedherein, the w/w percent of active agent in the encapsulated active agentis about 5%. In some embodiments of the devices, coatings and/or methodsprovided herein, the w/w percent of active agent in the encapsulatedactive agent is about 10-25%.

In some embodiments, the encapsulated active agent comprises a polymerat least partially encapsulating at least a portion of an active agentwherein the encapsulated active agent has a positive surface charge. Insome embodiments, the active agent is not completely encapsulated. Anactive agent (or a portion thereof) need not be completely surrounded inorder to be encapsulated by the polymer. In some embodiments, at least10%> of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 20%> of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 25% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 30% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 40% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 50% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 60% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 70% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 75% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 80% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 90% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 95% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast one of: at least 5% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 10%) of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 15% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 20% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 25% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 30% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 40% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 50% of the surfacearea of the active agent is at least partially surrounded by thepolymer₃ at least 60% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 70% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 75% of the surface area of the active agent is atleast partially surrounded by the polymer₃ at least 80% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 90% of the surface area of the active agent is atleast partially surrounded by the polymer, and at least 95% of thesurface area of the active agent is at least partially surrounded by thepolymer.

In some embodiments of the devices, coatings and/or methods providedherein, at least a portion of the encapsulated active agent arenanoparticles. At least a portion of the encapsulated active agent maybe at least one of: a spherical shape, a discoidal shape, ahemispherical shape, a cylindrical shape, a conical shape, a nanoreefshape, a nanobox shape, a cluster shape, a nanotube shape, a whiskershape, a rod shape, a fiber shape, a cup shape, a jack shape, ahexagonal shape, an ellipsoid shape, an oblate ellipsoid shape, aprolate ellipsoid shape, a torus shape, a spheroid shape, a taco-likeshape, a bullet shape, a barrel shape, a lens shape, a capsule shape, apulley wheel shape, a circular disc shape, a rectangular disc shape, ahexagonal disc shape, a flying saucer-like shape, a worm shape, aribbon-like shape, and a ravioli-like shape.

The active agent in some embodiments of the devices, coatings and/ormethods provided herein comprises a macrolide immunosuppressive drug.The active agent may be selected from sirolimus, a prodrug, a hydrate,an ester, a salt, a polymorph, a derivative, and an analog thereof. Aportion of the active agent may be in crystalline form.

The active agent may be, on average, at least one of: at most 5 microns,over 1 micrometer, between 1 micrometer and 5 micrometers, about 1.5micrometers on average, and about 2.5 micrometers on average. In someembodiments, the size of the active agent in the coating is controlledin order to improve drug retention in the artery. For non-limitingexample, in the case of sirolimus as an active agent, the sirolimus mayhave an average size of at least one of: 1.5 μηι, 2.5 μιη, 645 nm,100-200 nm, another controlled size, or a combination thereof. In someembodiments the size of the active agent is controlled. In someembodiments, the active agent is sirolimus and wherein the sirolimus hasa median size of at least one of: 1.5 μηι, 2.5 μιη, 645 nm, 100-200 nm,another controlled size, or a combination thereof. In some embodiments,the active agent is sirolimus and wherein the sirolimus has an averagesize of at least one of: about 1.5 μηι, about 2.5 μιη, about 645 nm,about 100-200 nm, another controlled size, or a combination thereof. Insome embodiments, the active agent is sirolimus and wherein thesirolimus has a median size of at least one of: about 1.5 μητ, about 2.5μιη, about 645 nm, about 100-200 nm, another controlled size, or acombination thereof. For example, in some embodiments, sirolimus is theactive agent and at least 75% of the sirolimus as is 1.5 μιη, 2.5 μιη,645 nm, 100-2(0) nm, or another controlled size. In some embodiments,sirolimus is the active agent and at least 50% of the sirolimus as is1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm, or another controlled size. Insome embodiments, sirolimus is the active agent and at least 90% of thesirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm, or anothercontrolled size. In some embodiments, sirolimus is the active agent andat least 95% of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200nm, or another controlled size. In some embodiments, sirolimus is theactive agent and at least 98% of the sirolimus as is 1.5 μιη, 2.5 μιη,645 nm, 100-200 nm, or another controlled size. In some embodiments,sirolimus is the active agent and at least 99% of the sirolimus as is1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm, or another controlled size.

In some embodiments of the devices, coatings and/or methods providedherein the coating delivers the active agent to the treatment site overat least about 1 day. In some embodiments of the devices, coatingsand/or methods provided herein the coating delivers the active agent tothe treatment site over at least one of: about 3 days, about 5 days,about 1 week, about 1.5 weeks, about 2 weeks, about 14 days, about 3weeks, about 21 days, about 4 weeks, about 28 days, about 1 month, about1.5 months, about 2 months, at least about 3 days, at least about 5days, at least about 1 week, at least about 1.5 weeks, at least about 2weeks, at least about 14 days, at least about 3 weeks, at least about 21days, at least about 4 weeks, at least about 28 days, at least about 1month, at least about 1.5 months, at least about 2 months, about 7 toabout 14 days, about 14 to about 21 days, about 14 to about 28 days,about 21 to about 28 days, and about 7 to about 28 days.

In some embodiments of the devices, coatings and/or methods providedherein the treatment site is a vessel wall. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is acoronary artery. In some embodiments of the devices, coatings and/ormethods provided herein the treatment site is bypass graft. In someembodiments of the devices, coatings and/or methods provided herein thetreatment site is a bifurcated lesion. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is asmall coronary lesions (for example, with reference diameter <2.5 mm).In some embodiments of the devices, coatings and/or methods providedherein the treatment site is a peripheral artery. In some embodiments ofthe devices, coatings and/or methods provided herein the treatment siteis vein. In some embodiments of the devices, coatings and/or methodsprovided herein the treatment site is an AV graft. In some embodimentsof the devices, coatings and/or methods provided herein the treatmentsite is an AV fistula. In some embodiments of the devices, coatingsand/or methods provided herein the treatment site is a biliary tract. Insome embodiments of the devices, coatings and/or methods provided hereinthe treatment site is a biliary duct. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is asinus. In some embodiments of the devices, coatings and/or methodsprovided herein the treatment site is a vein graft.

In some embodiments of the devices, coatings and/or methods providedherein the coating comprises a positive surface charge on a surface ofthe coating configured to contact the treatment site.

In some embodiments of the devices, coatings and/or methods providedherein the encapsulated active agent are micelles.

In some embodiments of the devices, coatings and/or methods providedherein the medical device comprises a balloon. In some embodiments themedical device is a balloon of a balloon catheter.

In some embodiments of the devices, coatings and/or methods providedherein depositing the encapsulated active agent comprises using an eSTATprocess. In some embodiments of the devices, coatings and/or methodsprovided herein depositing a second polymer on the medical devicefollowing depositing the encapsulated active agent on the medicaldevice.

In some embodiments of the methods and/or devices provided herein, thecoating is formed on the substrate by a process comprising depositing apolymer and/or the active agent by an RESS, e-RESS, an e-SEDS, or ane-DPC process. In some embodiments of the methods and/or devicesprovided herein, wherein the coating is formed on the substrate by aprocess comprising at least one of: depositing a polymer by an RESS,e-RESS, an e-SEDS, or an e-DPC process, and depositing thepharmaceutical agent by an e-RESS, an e-SEDS, eSTAT, or an e-DPCprocess. In some embodiments of the methods and/or devices providedherein, the coating is formed on the substrate by a process comprisingat least one of: depositing a polymer by an RESS, e-RESS, an e-SEDS, oran e-DPC process, and depositing the active agent by an eSTAT, e-RESS,an c-SEDS, or an e-DPC process. In some embodiments, the process offorming the coating provides improved adherence of the coating to thesubstrate prior to deployment of the device at the intervention site andfacilitates dissociation of the coating from the substrate at theintervention site. In some embodiments, the coating is formed on thesubstrate by a process comprising depositing the active agent by aneSTAT, e-RESS, an e-SEDS, or an e-DPC process without electricallycharging the substrate. In some embodiments, the coating is formed onthe substrate by a process comprising depositing the active agent on thesubstrate by an e-RESS, an e-SEDS, or an e-DPC process without creatingan electrical potential between the substrate and a coating apparatusused to deposit the coating.

In some embodiments of the devices, coatings and/or methods providedherein the second polymer comprises PLGA. The PLGA may have at least oneof: a MW of about 30 KDa and a Mn of about 15 KDa, a Mn of about 10 KDato about 25 KDa, and a MW of about 15 KDa to about 40 KDa. Depositingthe second polymer on the medical device may use at least one of a RESScoating process, an eSTAT coating process, a dip coating process, and aspray coating process.

In some embodiments of the methods and/or devices provided herein, theintervention site is in or on the body of a subject. In someembodiments, the intervention site is a vascular wall. In someembodiments, the intervention site is a non-vascular lumen wall. In someembodiments, the intervention site is a vascular cavity wall. In someembodiments of the methods and/or devices provided herein, theintervention site is a wall of a body cavity. In some embodiments, thebody cavity is the result of a lumpectomy. In some embodiments, theintervention site is a cannulized site within a subject. In someembodiments of the methods and/or devices provided herein, theintervention site is a sinus wall. In some embodiments, the interventionsite is a sinus cavity wall. In some embodiments, the active agentcomprises a corticosteroid.

In some embodiments of the methods and/or devices provided herein, thecoating is capable of at least one of: retarding healing, delayinghealing, and preventing healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing theinflammatory phase of healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing theproliferative phase of healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing thematuration phase of healing. In some embodiments, the coating is capableof at least one of: retarding, delaying, and preventing the remodelingphase of healing. In some embodiments, the active agent comprises ananti-angiogenic agent.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andtransferring at least a portion of the coating from the substrate to theintervention site upon stimulating the coating with a stimulation.

Provided herein is a medical device comprising: an invertable balloon;and a coating on an abluminal side of the invertable balloon, whereinthe coating comprises an active agent and a binding agent, and whereinthe device releases at least 3% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the balloon isinverted such that the abluminal side of the balloon is protected fromblood flow during tracking to the treatment site. In some embodiments,the balloon is inverted such that the abluminal side of the balloon isprotected from blood flow during tracking to the treatment site. In someembodiments, the balloon is inverted on the outside of the catheter. Insome embodiments, the balloon is capable of being un-inverted such thatthe abluminal surface is positioned within the treatment site. In someembodiments, the balloon is inverted within a catheter. In someembodiments, the balloon is capable of being pushed out of the catheterusing balloon inflation pressure. In some embodiments, the balloon iscapable of being pushed out of the catheter by moving the distal end ofthe balloon distally through the balloon. In some embodiments, theballoon unrolls into the treatment site such that the coated portion ofthe balloon is adjacent the treatment site. In some embodiments, theballoon is partially un-inverted at the treatment site. In someembodiments, the treatment length of the balloon is controlled bypartially un-inverting balloon outside of a catheter in which it wasinverted.

Provided herein is method comprising providing an invertable ballooncomprising a coating on an abluminal side of the invertable balloon,wherein the coating comprises an active agent and a binding agent, andun-inverting the invertable balloon to expose the coating or a portionthereof to a treatment site, wherein the device releases at least 3% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the abluminal side of the balloon is protected fromblood flow during tracking to the treatment site. In some embodiments,the balloon is inverted on the outside of the catheter. In someembodiments, the balloon is capable of being un-inverted such that theabluminal surface is positioned within the treatment site. In someembodiments, the balloon is inverted within a catheter. In someembodiments, the balloon is capable of being pushed out of the catheterusing balloon inflation pressure. In some embodiments, the balloon iscapable of being pushed out of the catheter by moving the distal end ofthe balloon distally through the balloon. In some embodiments, theballoon unrolls into the treatment site such that the coated portion ofthe balloon is adjacent the treatment site. The method may comprisepartially un-inverting the balloon at the treatment site. The method maycomprise controlling a treatment length of the balloon by partiallyun-inverting balloon outside of a catheter in which it was inverted.

Provided herein is a medical device comprising: a balloon; and a coatingon an abluminal side of the balloon, a sheath over the balloon whereinthe coating comprises an active agent and a binding agent, and whereinthe device releases at least 3% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the sheath isretractable. In some embodiments, the sheath covers the coated balloonuntil the balloon reaches the treatment site. In some embodiments, thesheath is retractable once the coated balloon is positioned near thetreatment site. In some embodiments, the sheath is retractable once thecoated balloon is positioned at the treatment site. In some embodiments,the sheath covers the coated balloon until the balloon is proximal tothe treatment site. In some embodiments, the sheath covers the coatedballoon until the balloon is distal to the treatment site. In someembodiments, the sheath covers the coated balloon until the balloon iswithin to the treatment site. In some embodiments, the sheath may bemoved over the balloon following deflation of the balloon after thecoating has been released to the artery. In some embodiments, the sheathmay be moved over the balloon following deflation of the balloon after aportion of the coating has been released to the artery.

Provided herein is method comprising: providing a balloon comprising acoating on an abluminal side of the balloon, and providing a sheath overthe balloon, wherein the coating comprises an active agent and a bindingagent, and wherein the device releases at least 3% of the active agentto artery upon inflation of the balloon in vivo. The method may compriseretracting the sheath. The method may comprise keeping the sheath overthe balloon until the balloon reaches the treatment site. The method maycomprise keeping the sheath over the balloon until the coated balloon ispositioned near the treatment site. The method may comprise keeping thesheath over the balloon until the coated balloon is positioned at thetreatment site. The method may comprise keeping the sheath over theballoon until the balloon is proximal to the treatment site. The methodmay comprise keeping the sheath over the balloon until the balloon isdistal to the treatment site. The method may comprise keeping the sheathover the balloon until the balloon is within to the treatment site. Themethod may comprise moving the sheath over the balloon after the coatinghas been released to the artery. The method may comprise moving thesheath over the balloon after a portion of the coating has been releasedto the artery.

Provided herein is a medical device comprising: a balloon; and a coatingon the balloon, and an occluder, wherein the coating comprises an activeagent and a binding agent, and wherein the device releases at least 3%of the active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the occluder is a flow occluder. In some embodiments,the occluder configured to block the flow of bodily fluids at atreatment site during exposure of the coating to the treatment site. Insome embodiments, the occluder comprises a second balloon that occludesthe flow of the blood at the treatment site. In some embodiments, theballoon comprises the occluder. In some embodiments, the balloon has twosections, a first section comprising the occluder and a second sectioncomprising the coating. In some embodiments, the balloon comprises adistal node and a proximal node. In some embodiments, the distal nodecomprises the coating and wherein the proximal node comprises theoccluder. In some embodiments, the proximal node comprises the coatingand wherein the distal node comprises the occluder. In some embodiments,the occluder is located proximally from the balloon. In someembodiments, the occluder is located proximally from the coating. Insome embodiments, the occluder is the appropriate shape to occlude flowof blood at the treatment site. In some embodiments, the occludersubstantially conforms to the shape of a treatment area near a treatmentsite such fluid flow at the treatment site is occluded. In someembodiments, a distal portion of the balloon is coated and wherein aproximal portion of the balloon is not coated, and wherein the proximalportion of the balloon is the occluder. In some embodiments, a proximalportion of the balloon is coated and wherein a distal portion of theballoon is not coated, and wherein the distal portion of the balloon isthe occluder. In some embodiments, a second balloon comprises theoccluder. In some embodiments, the balloon and the second balloon haveseparate inflation lumens. In some embodiments, the balloon and thesecond balloon share an inflation lumen. In some embodiments, theoccluder is located proximally from the coating. In some embodiments,the occluder is located distally from the coating. In some embodiments,the occluder occludes the flow of the fluid at the treatment prior toexpansion of the balloon having coating thereon. In some embodiments,the occluder is deployable. In some embodiments, the occluder isdeployable separately from the balloon. In some embodiments, the heoccluder is retractable. In some embodiments, the occluder comprises asecond coating. In some embodiments, the second coating comprises atleast one of an active agent and a polymer.

Provided herein is method comprising providing a balloon comprising acoating on the balloon, wherein the coating comprises an active agentand a binding agent, providing an occluder, wherein the device releasesat least 3% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the occluder is a flow occluder. In someembodiments, the occluder configured to block the flow of bodily fluidsat a treatment site during exposure of the coating to the treatmentsite. In some embodiments, the occluder comprises a second balloon thatoccludes the flow of the blood at the treatment site. In someembodiments, the balloon comprises the occluder. In some embodiments,the balloon has two sections, a first section comprising the occluderand a second section comprising the coating. In some embodiments, theballoon comprises a distal node and a proximal node. In someembodiments, the distal node comprises the coating and wherein theproximal node comprises the occluder. In some embodiments, the proximalnode comprises the coating and wherein the distal node comprises theoccluder. In some embodiments, the occluder is located proximally fromthe balloon. In some embodiments, the occluder is located proximallyfrom the coating. In some embodiments, the occluder is the appropriateshape to occlude flow of blood at the treatment site. In someembodiments, the occluder substantially conforms to the shape of atreatment area near a treatment site such fluid flow at the treatmentsite is occluded. In some embodiments, a distal portion of the balloonis coated and wherein a proximal portion of the balloon is not coated,and wherein the proximal portion of the balloon is the occluder. In someembodiments, a proximal portion of the balloon is coated and wherein adistal portion of the balloon is not coated, and wherein the distalportion of the balloon is the occluder. In some embodiments, a secondballoon comprises the occluder. In some embodiments, the balloon and thesecond balloon have separate inflation lumens. In some embodiments, theballoon and the second balloon share an inflation lumen. In someembodiments, the occluder is located proximally from the coating. Insome embodiments, the occluder is located distally from the coating. Insome embodiments, the occluder occludes the flow of fluid at a treatmentprior to expansion of the balloon having coating thereon. The method maycomprise deploying the occluder. In some embodiments, the occluder isdeployable separately from the balloon. The method may compriseretracting the occluder. In some embodiments, the occluder comprises asecond coating. In some embodiments, the second coating comprises atleast one of an active agent and a polymer.

In some embodiments of the devices, methods or coatings herein, thedevice releases at least one of: at least 5% of the active agent toartery upon inflation of the balloon in vivo, at least 7% of the activeagent to artery upon inflation of the balloon in vivo, at least 10% ofthe active agent to artery upon inflation of the balloon in vivo, atleast 15% of the active agent to artery upon inflation of the balloon invivo, at least 20% of the active agent to artery upon inflation of theballoon in vivo, at least 25% of the active agent to artery uponinflation of the balloon in vivo, at least 25% of the active agent toartery upon inflation of the balloon in vivo, at least 30% of the activeagent to artery upon inflation of the balloon in vivo, at least 40% ofthe active agent to artery upon inflation of the balloon in vivo, atleast 50% of the active agent to artery upon inflation of the balloon invivo, between 2% and 50% of the active agent to artery upon inflation ofthe balloon in vivo, between 3% and 50% of the active agent to arteryupon inflation of the balloon in vivo, between 5% and 50% of the activeagent to artery upon inflation of the balloon in vivo, between 3% and30% of the active agent to artery upon inflation of the balloon in vivo,between 3% and 25% of the active agent to artery upon inflation of theballoon in vivo, between 3% and 20% of the active agent to artery uponinflation of the balloon in vivo, between 3% and 15% of the active agentto artery upon inflation of the balloon in vivo, between 1% and 15% ofthe active agent to artery upon inflation of the balloon in vivo,between 1% and 10% of the active agent to artery upon inflation of theballoon in vivo, between 3% and 10% of the active agent to artery uponinflation of the balloon in vivo, and between 1% and 5% of the activeagent to artery upon inflation of the balloon in vivo.

In some embodiments of the devices, methods or coatings herein, at leastone of: at most 1% of coating is removed from the balloon due totracking of the coated balloon to the treatment site, at most 5% ofcoating is removed from the balloon due to tracking of the coatedballoon to the treatment site, at most 10%) of coating is removed fromthe balloon due to tracking of the coated balloon to the treatment site,at most 15% of coating is removed from the balloon due to tracking ofthe coated balloon to the treatment site, at most 20% of coating isremoved from the balloon due to tracking of the coated balloon to thetreatment site, at most 25% of coating is removed from the balloon dueto tracking of the coated balloon to the treatment site, and at most 30%of coating is removed from the balloon due to tracking of the coatedballoon to the treatment site.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference. This applicationrelates to U.S. Provisional Application No. 61/081,691, filed Jul. 17,2008, U.S. Provisional Application No. 61/226,239 filed Jul. 16, 2009,U.S. Provisional Application No. 61/212,964, filed Apr. 17, 2009, U.S.application Ser. No. 12/504,597, filed Jul. 16, 2009, U.S. applicationSer. No. 12/729,580, filed Mar. 23, 2010, PCT Application No.PCT/US2009/050883, filed Jul. 16, 2009, PCT Application No.PCT/US2010/028253, filed Mar. 23, 2010, and PCT Application No.PCT/US2010/042355, filed Jul. 16, 2010. The contents of theseapplications are incorporated herein by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 indicates the Average percent Sirolimus Eluted from the balloonsat various time points for Formulations F3, F5, and F7.

FIG. 2 depicts an example eSTAT process for coating 12 angioplastyballoons with sirolimus.

FIG. 3 depicts coating balloons according to an RESS process.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in greater detail below. Thisdescription is not intended to be a detailed catalog of all thedifferent ways in which the invention may be implemented, or all thefeatures that may be added to the instant invention. For example,features illustrated with respect to one embodiment may be incorporatedinto other embodiments, and features illustrated with respect to aparticular embodiment may be deleted from that embodiment. In addition,numerous variations and additions to the various embodiments suggestedherein will be apparent to those skilled in the art in light of theinstant disclosure, which do not depart from the instant invention.Hence, the following specification is intended to illustrate someparticular embodiments of the invention, and not to exhaustively specifyall permutations, combinations and variations thereof.

Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

“Substrate” as used herein, refers to any surface upon which it isdesirable to deposit a coating. Biomedical implants are of particularinterest for the present invention; however the present invention is notintended to be restricted to this class of substrates. Those of skill inthe art will appreciate alternate substrates that could benefit from thecoating process described herein, such as pharmaceutical tablet cores,as part of an assay apparatus or as components in a diagnostic kit(e.g., a test strip).

Examples of substrates that can be coated using the methods of theinvention include surgery devices or medical devices, e.g., a catheter,a balloon, a cutting balloon, a wire guide, a cannula, tooling, anorthopedic device, a structural implant, stent, stent-graft, graft, venacava filter, a heart valve, cerebrospinal fluid shunts, pacemakerelectrodes, axius coronary shunts, endocardial leads, an artificialheart, and the like.

“Biomedical implant” as used herein refers to any implant for insertioninto the body of a human or animal subject, including but not limited tostents (e.g., coronary stents, vascular stents including peripheralstents and graft stents, urinary tract stents, urethral/prostaticstents, rectal stent, oesophageal stent, biliary stent, pancreaticstent), electrodes, catheters, leads, implantable pacemaker,cardioverter or defibrillator housings, joints, screws, rods, ophthalmicimplants, femoral pins, bone plates, grafts, anastomotic devices,perivascular wraps, sutures, staples, shunts for hydrocephalus, dialysisgrafts, colostomy bag attachment devices, ear drainage tubes, leads forpace makers and implantable cardioverters and defibrillators, vertebraldisks, bone pins, suture anchors, hemostatic barriers, clamps, screws,plates, clips, vascular implants, tissue adhesives and sealants, tissuescaffolds, various types of dressings (e.g., wound dressings), bonesubstitutes, intraluminal devices, vascular supports, etc.

The implants may be formed from any suitable material, including but notlimited to polymers (including stable or inert polymers, organicpolymers, organic-inorganic copolymers, inorganic polymers, andbiodegradable polymers), metals, metal alloys, inorganic materials suchas silicon, and composites thereof, including layered structures with acore of one material and one or more coatings of a different material.Substrates made of a conducting material facilitate electrostaticcapture. However, the invention contemplates the use of electrostaticcapture, as described herein, in conjunction with substrate having lowconductivity or which are non-conductive. To enhance electrostaticcapture when a non-conductive substrate is employed, the substrate isprocessed for example while maintaining a strong electrical field in thevicinity of the substrate. In some embodiments, however, noelectrostatic capture is employed in applying a coating to thesubstrate. In some embodiments of the methods and/or devices providedherein, the substrate is not charged in the coating process. In someembodiments of the methods and/or devices provided herein, an electricalpotential is not created between the substrate and the coatingapparatus.

Subjects into which biomedical implants of the invention may be appliedor inserted include both human subjects (including male and femalesubjects and infant, juvenile, adolescent, adult and geriatric subjects)as well as animal subjects (including but not limited to pig, rabbit,mouse, dog, cat, horse, monkey, etc.) for veterinary purposes and/ormedical research.

As used herein, a biological implant may include a medical device thatis not permanently implanted. A biological implant in some embodimentsmay comprise a device which is used in a subject on a transient basis.For non-limiting example, the biomedical implant may be a balloon, whichis used transiently to dilate a lumen and thereafter may be deflatedand/or removed from the subject during the medical procedure orthereafter. In some embodiments, the biological implant may betemporarily implanted for a limited time, such as during a portion of amedical procedure, or for only a limited time (some time less thanpermanently implanted), or may be transiently implanted and/ormomentarily placed in the subject. In some embodiments, the biologicalimplant is not implanted at all, rather it is merely inserted into asubject during a medical procedure, and subsequently removed from thesubject prior to or at the time the medical procedure is completed. Insome embodiments, the biological implant is not permanently implantedsince it completely resorbs into the subject (i.e. is completelyresorbed by the subject). In a preferred embodiment the biomedicalimplant is an expandable balloon that can be expanded within a lumen(naturally occurring or non-naturally occurring) having a coatingthereon that is freed (at least in part) from the balloon and leftbehind in the lumen when the balloon is removed from the lumen.

Examples of pharmaceutical agents employed in conjunction with theinvention include, rapamycin, 40-O-(2-Hydroxyethyl)rapamycin(everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 40-O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5-Dicarboethoxy-,2′,3′-triazol-1-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus). The active agent in some embodiments of the devices,coatings and/or methods provided herein comprises a macro lideimmunosuppressive drug. In some embodiments the macrolideimmunosuppressive drug comprises one or more of rapamycin,40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4'S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 40-O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin40-0-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-0-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus). The active agent may be selected from a macrolideimmunosuppressive drug, a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative, and an analog thereof. The active agent may beselected from sirolimus, a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative, and an analog thereof.

The pharmaceutical agents may, if desired, also be used in the form oftheir pharmaceutically acceptable salts or derivatives (meaning saltswhich retain the biological effectiveness and properties of thecompounds of this invention and which are not biologically or otherwiseundesirable), and in the case of chiral active ingredients it ispossible to employ both optically active isomers and racemates ormixtures of diastereoisomers. As well, the pharmaceutical agent mayinclude at least one of: a prodrug, a hydrate, an ester, a salt, apolymorph, a derivative, and an analog thereof.

The pharmaceutical agent may be an antibiotic agent, as describedherein.

In some embodiments of the methods, coatings, and/or devices providedherein, the size of the active agent in the coating is controlled. Insome embodiments, the active agent is sirolimus and wherein thesirolimus has an average size (mean diameter) of at least one of: 1.5μητ, 2.5 μιη, 645 nm, 100-200 nm, another controlled size, or acombination thereof. In some embodiments, the active agent is sirolimusand wherein the sirolimus has a median size of at least one of: 1.5 μηι,2.5 μηι, 645 nm, 100-200 nm, another controlled size, or a combinationthereof. In some embodiments, the active agent is sirolimus and whereinthe sirolimus has an average size (mean diameter) of at least one of:about 1.5 μηι, about 2.5 μηι, about 645 nm, about 100-200 nm, anothercontrolled size, or a combination thereof. In some embodiments, theactive agent is sirolimus and wherein the sirolimus has a median size ofat least one of: about 1.5 μηι, about 2.5 μηι, about 645 nm, about100-200 nm, another controlled size, or a combination thereof. In someembodiments, the active agent is sirolimus and wherein sirolimus atleast 75% of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm,or another controlled size. In some embodiments, the active agent issirolimus and wherein sirolimus at least 50% of the sirolimus as is 1.5μιη, 2.5 μιη, 645 nm, 100-200 nm, or another controlled size. In someembodiments, the active agent is sirolimus and wherein sirolimus atleast 90%> of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm,or another controlled size.

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 50% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 75% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 90%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 95% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 97% crystalline. In some embodiments ofthe methods and/or devices provided herein pharmaceutical agent is atleast 98% crystalline. In some embodiments of the methods and/or devicesprovided herein the pharmaceutical agent is at least 99% crystalline.

“Prodrugs” are derivative compounds derivatized by the addition of agroup that endows greater solubility to the compound desired to bedelivered. Once in the body, the prodrug is typically acted upon by anenzyme, e.g., an esterase, amidase, or phosphatase, to generate theactive compound.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.There are many chemotherapeutic agents available in commercial use, inclinical evaluation and in pre-clinical development that are useful inthe devices and methods of the present invention for treatment ofcancers.

“Stability” as used herein in refers to the stability of the drug in acoating deposited on a substrate in its final product form (e.g.,stability of the drug in a coated stent). The term “stability” and/or“stable” in some embodiments is defined by 5% or less degradation of thedrug in the final product form. The term stability in some embodimentsis defined by 3% or less degradation of the drug in the final productform. The term stability in some embodiments is defined by 2% or lessdegradation of the drug in the final product form. The term stability insome embodiments is defined by 1% or less degradation of the drug in thefinal product form.

In some embodiments, the pharmaceutical agent is at least one of: 50%crystalline, 75% crystalline, 80% crystalline, 90% crystalline, 95%crystalline, 97% crystalline, and 99% crystalline followingsterilization of the device. In some embodiments, the pharmaceuticalagent crystallinity is stable wherein the crystallinity of thepharmaceutical agent following sterilization is compared to thecrystallinity of the pharmaceutical agent at least one of: 1 week aftersterilization, 2 weeks after sterilization, 4 weeks after sterilization,1 month after sterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization. In some embodiments, the pharmaceutical agentcrystallinity is stable wherein the crystallinity of the pharmaceuticalagent prior to sterilization is compared to the crystallinity of thepharmaceutical agent at least one of: 1 week after sterilization, 2weeks after sterilization, 4 weeks after sterilization, 1 month aftersterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization. In such embodiments, different devices may be tested fromthe same manufacturing lot to determine stability of the pharmaceuticalagent at the desired time points.

In some embodiments, the pharmaceutical agent crystallinity is stable atleast one of: 1 week after sterilization, 2 weeks after sterilization, 4weeks after sterilization, 1 month after sterilization, 2 months aftersterilization, 45 days after sterilization, 60 days after sterilization,90 days after sterilization, 3 months after sterilization, 4 monthsafter sterilization, 6 months after sterilization, 9 months aftersterilization, 12 months after sterilization, 18 months aftersterilization, and 2 years after sterilization.

In some embodiments, the pharmaceutical agent crystallinity on thedevice tested at a time point after sterilization does not differ morethan 1%, 2%, 3%, 4%, and/or 5% from the crystallinity tested on a seconddevice manufactured from the same lot of devices and the same lot ofpharmaceutical agent at testing time point before sterilization (i.e.the crystallinity drops no more than from 99 to 94% crystalline, forexample, which is a 5% difference in crystallinity; the crystallinitydrops no more than from 99 to 95% crystalline, which is a 4% differencein crystallinity; the crystallinity drops no more than from 99 to 96%crystalline, for example, which is a 3% difference in crystallinity; thecrystallinity drops no more than from 99 to 97% crystalline, forexample, which is a 2% difference in crystallinity; the crystallinitydrops no more than from 99 to 98% crystalline, for example, which is a1% difference in crystallinity; in other examples, the startingcrystallinity percentage is one of 100%, 98%, 96%, 97%, 96%, 95%, 90%,85%, 80%, 75%, 70%, 60%, 50%, 30%, 25%, and/or anything in between).

In some embodiments, crystallinity of the pharmaceutical agent on thedevice tested at a time point after sterilization does not differ morethan 1%, 2%, 3%, 4%, and/or 5% from the crystallinity of pharmaceuticalfrom the same lot of pharmaceutical agent tested at testing time pointbefore sterilization of the pharmaceutical agent.

In some embodiments, crystallinity of the pharmaceutical agent does notdrop more than 1%, 2%, 3%, 4%, and/or 5% between two testing time pointsafter sterilization neither of which time point being greater than 2years after sterilization. In some embodiments, crystallinity of thepharmaceutical agent does not drop more than 1%, 2%, 3%, 4%, and/or 5%between two testing time points after sterilization neither of whichtime point being greater than 5 years after sterilization. In someembodiments, two time points comprise two of: 1 week aftersterilization, 2 weeks after sterilization, 4 weeks after sterilization,1 month after sterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, 2 years aftersterilization, 3 years after sterilization, 4 years after sterilization,and 5 years after sterilization.

“Polymer” as used herein, refers to a series of repeating monomericunits that have been cross-linked or polymerized. Any suitable polymercan be used to carry out the present invention. It is possible that thepolymers of the invention may also comprise two, three, four or moredifferent polymers. In some embodiments of the invention only onepolymer is used. In certain embodiments a combination of two polymers isused. Combinations of polymers can be in varying ratios, to providecoatings with differing properties, Polymers useful in the devices andmethods of the present invention include, for example, stable or inertpolymers, organic polymers, organic-inorganic copolymers, inorganicpolymers, bioabsorbable, bioresorbable, resorbable, degradable, andbiodegradable polymers. Those of skill in the art of polymer chemistrywill be familiar with the different properties of polymeric compounds.

In some embodiments, the coating further comprises a polymer. In someembodiments, the active agent comprises a polymer. In some embodiments,the polymer comprises at least one of polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, polyurethanes,polyanhydrides, aliphatic polycarbonates, polyhydroxyalkanoates,silicone containing polymers, polyalkyl siloxanes, aliphatic polyesters,polyglycolides, polylactides, polylactide-co-glycolides,poly(e-caprolactone)s, polytetrahalooalkylenes, polystyrenes,poly(phosphasones), copolymers thereof, and combinations thereof.

In embodiments, the polymer is capable of becoming soft afterimplantation, for example, due to hydration, degradation or by acombination of hydration and degradation. In embodiments, the polymer isadapted to transfer, free, and/or dissociate from the substrate when atthe intervention site due to hydrolysis of the polymer. In variousembodiments, the device is coated with a bioabsorbable polymer that iscapable of resorbtion in at least one of: about 1 day, about 3 days,about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks,about 45 days, about 60 days, about 90 days, about 180 days, about 6months, about 9 months, about 1 year, about 1 to about 2 days, about 1to about 5 days, about 1 to about 2 weeks, about 2 to about 4 weeks,about 45 to about 60 days, about 45 to about 90 days, about 30 to about90 days, about 60 to about 90 days, about 90 to about 180 days, about 60to about 180 days, about 180 to about 365 days, about 6 months to about9 months, about 9 months to about 12 months, about 9 months to about 15months, and about 1 year to about 2 years.

Examples of polymers that may be used in the present invention include,but are not limited to polycarboxylic acids, cellulosic polymers,proteins, polypeptides, polyvinylpyrrolidone, maleic anhydride polymers,polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans,polysaccharides, polyesters, aliphatic polyesters, polyurethanes,polystyrenes, copolymers, silicones, silicone containing polymers,polyalkyl siloxanes, polyorthoesters, polyanhydrides, copolymers ofvinyl monomers, polycarbonates, polyethylenes, polypropytenes,polylactic acids, polylactides, polyglycolic acids, polyglycolides,polylactide-co-glycolides, polycaprolactones, poly(e-caprolactone)s,polyhydroxybutyrate valerates, polyacrylamides, polyethers, polyurethanedispersions, polyacrylates, acrylic latex dispersions, polyacrylic acid,polyalkyl methacrylates, polyalkylene-co-vinyl acetates, polyalkylenes,aliphatic polycarbonates polyhydroxyalkanoates, polytetrahalooalkylenes,poly(phosphasones), polytetrahalooalkylenes, poly(phosphasones), andmixtures, combinations, and copolymers thereof.

The polymers of the present invention may be natural or synthetic inorigin, including gelatin, chitosan, dextrin, cyclodextrin,Poly(urethanes), Poly(siloxanes) or silicones, Poly(acrylates) such as[rho]oly(methyl methacrylate), poly(butyl methacrylate), andPoly(2-hydroxy ethyl methacrylate), Poly(vinyl alcohol) Poly(olefins)such as poly(ethylene), [rho]oly(isoprene), halogenated polymers such asPoly(tetrafluoroethylene)—and derivatives and copolymers such as thosecommonly sold as Teflon® products, Poly(vinylidine fluoride), Poly(vinylacetate), Poly(vinyl pyrrolidone), Poly(acrylic acid) Polyacrylamide,Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol), Poly(propyleneglycol), Poly(methacrylic acid); etc.

Suitable polymers also include absorbable and/or resorbable polymersincluding the following, combinations, copolymers and derivatives of thefollowing: Polylactides (PLA), Polyglycolides (PGA),Polylactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl) methacrylamide), Poly(1-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(1-lactide):PDO—poly(dioxanone): PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

In some embodiments of the devices, coatings and/or methods providedherein the polymer comprises PLGA. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises about 50:50Lactic acid:Glycolic acid. The PLGA may have at least one of: a MW ofabout 30 KDa and a Mn of about 15 KDa, a Mn of about 10 KDa to about 25KDa, and a MW of about 15 KDa to about 40 KDa. In some embodiments ofthe methods, coatings, or devices provided herein, the PLGA comprises50:50 Lactic acid:Glycolic acid. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises from 40:60 to60:40 Lactic acid:Glycolic acid. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises from 45:55 to55:45 Lactic acid:Glycolic acid. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises from 48:52 to52:48 Lactic acid:Glycolic acid. In some embodiments of the methods,coatings, or devices provided herein, the PLGA comprises from 49:51 to51:49 Lactic acid:Glycolic acid. The use of the term “about” with regardto the ratio of Lactic acid to Glycolic acid in the PLGA, as usedherein, refers to ranges of ratios from 40:60 to 60:40, or from 45:55 to55:45, or from 48:52 to 52:48 or from 49:51 to 51:49, depending on theembodiment.

“Copolymer” as used herein refers to a polymer being composed of two ormore different monomers. A copolymer may also and/or alternatively referto random, block, graft, copolymers known to those of skill in the art.

“Biocompatible” as used herein, refers to any material that does notcause injury or death to the animal or induce an adverse reaction in ananimal when placed in intimate contact with the animal's tissues.Adverse reactions include for example inflammation, infection, fibrotictissue formation, cell death, or thrombosis. The terms “biocompatible”and “biocompatibility” when used herein are art-recognized and mean thatthe referent is neither itself toxic to a host (e.g., an animal orhuman), nor degrades (if it degrades) at a rate that produces byproducts(e.g., monomeric or oligomeric subunits or other byproducts) at toxicconcentrations, causes inflammation or irritation, or induces an immunereaction in the host. It is not necessary that any subject compositionhave a purity of 100% to be deemed biocompatible. Hence, a subjectcomposition may comprise 99%, 98%, 97%, 96%, 95%, 90%) 85%), 80%), 75%)or even less of biocompatible agents, e.g., including polymers and othermaterials and excipients described herein, and still be biocompatible.“Non-biocompatible” as used herein, refers to any material that maycause injury or death to the animal or induce an adverse reaction in theanimal when placed in intimate contact with the animal's tissues. Suchadverse reactions are as noted above, for example.

The terms “bioabsorbable,” “biodegradable,” “bioerodible,”“bioresorbable,” and “resorbable” are art-recognized synonyms. Theseterms are used herein interchangeably. Bioabsorbable polymers typicallydiffer from non-bioabsorbable polymers in that the former may beabsorbed (e.g.; degraded) during use. In certain embodiments, such useinvolves in vivo use, such as in vivo therapy, and in other certainembodiments, such use involves in vitro use. In general, degradationattributable to biodegradability involves the degradation of abioabsorbable polymer into its component subunits, or digestion, e.g.,by a biochemical process, of the polymer into smaller, non-polymericsubunits. In certain embodiments, biodegradation may occur by enzymaticmediation, degradation in the presence of water (hydrolysis) and/orother chemical species in the body, or both. The bioabsorbability of apolymer may be indicated in-vitro as described herein or by methodsknown to one of skill in the art. An in-vitro test for bioabsorbabilityof a polymer does not require living cells or other biologic materialsto indicate bioabsorption properties (e.g., degradation, digestion).Thus, resorbtion, resorption, absorption, absorption, erosion may alsobe used synonymously with the terms “bioabsorbable,” “biodegradable,”“bioerodible,” and “bioresorbable.” Mechanisms of degradation of abioabsorbable polymer may include, but are not limited to, bulkdegradation, surface erosion, and combinations thereof.

As used herein, the term “biodegradation” encompasses both general typesof biodegradation. The degradation rate of a biodegradable polymer oftendepends in part on a variety of factors, including the chemical identityof the linkage responsible for any degradation, the molecular weight,crystallinity, biostability, and degree of cross-linking of suchpolymer, the physical characteristics (e.g., shape and size) of theimplant, and the mode and location of administration. For example, thegreater the molecular weight, the higher the degree of crystallinity,and/or the greater the biostability, the biodegradation of anybioabsorbable polymer is usually slower.

“Degradation” as used herein refers to the conversion or reduction of achemical compound to one less complex, e.g., by splitting off one ormore groups of atoms. Degradation of the coating may reduce thecoating's cohesive and adhesive binding to the device, therebyfacilitating transfer of the coating to the intervention site.

“Therapeutically desirable morphology” as used herein refers to thegross form and structure of the pharmaceutical agent, once deposited onthe substrate, so as to provide for optimal conditions of ex vivostorage, in vivo preservation and/or in vivo release. Such optimalconditions may include, but are not limited to increased shelf life(i.e., shelf stability), increased in vivo stability, goodbiocompatibility, good bioavailability or modified release rates.Typically, for the present invention, the desired morphology of apharmaceutical agent would be crystalline or semi-crystalline oramorphous, although this may vary widely depending on many factorsincluding, but not limited to, the nature of the pharmaceutical agent,the disease to be treated/prevented, the intended storage conditions forthe substrate prior to use or the location within the body of anybiomedical implant. Preferably at least 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5%, and/or 100)% of thepharmaceutical agent is in crystalline or semi-crystalline form.

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided hereinwherein the pharmaceutical agent is at least 50% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 75% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 95%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 97% crystalline. In someembodiments of the methods and/or devices provided herein pharmaceuticalagent is at least 98% crystalline. In some embodiments of the methodsand/or devices provided herein the pharmaceutical agent is at least 99%crystalline.

“Stabilizing agent” as used herein refers to any substance thatmaintains or enhances the stability of the biological agent. Ideallythese stabilizing agents are classified as Generally Regarded As Safe(GRAS) materials by the US Food and Drug Administration (FDA). Examplesof stabilizing agents include, but are not limited to carrier proteins,such as albumin, gelatin, metals or inorganic salts. Pharmaceuticallyacceptable excipient that may be present can further be found in therelevant literature, for example in the Handbook of PharmaceuticalAdditives: An International Guide to More Than 6000 Products by TradeName, Chemical, Function, and Manufacturer; Michael and Irene Ash(Eds.); Gower Publishing Ltd.; Aldershot, Hampshire, England, 1995.

“Intervention site” as used herein refers to the location in the bodywhere the coating is intended to be delivered (by transfer from, freeingfrom, and/or dissociating from the substrate). The intervention site canbe any substance in the medium surrounding the device, e.g., tissue,cartilage, a body fluid, etc. The intervention site can be the same asthe treatment site, i.e., the substance to which the coating isdelivered is the same tissue that requires treatment. Alternatively, theintervention site can be separate from the treatment site, requiringsubsequent diffusion or transport of the pharmaceutical or other agentaway from the intervention site.

“Compressed fluid” as used herein refers to a fluid of appreciabledensity (e.g., >0.2 g/cc) that is a gas at standard temperature andpressure. “Supercritical fluid,” “near-critical fluid,”“near-supercritical fluid,” “critical fluid,” “densified fluid,” or“densified gas,” as used herein refers to a compressed fluid underconditions wherein the temperature is at least 80% of the criticaltemperature of the fluid and the pressure is at least 50% of thecritical pressure of the fluid, and/or a density of +50% of the criticaldensity of the fluid.

Examples of substances that demonstrate supercritical or near criticalbehavior suitable for the present invention include, but are not limitedto carbon dioxide, isobutylene, ammonia, water, methanol, ethanol,ethane, propane, butane, pentane, dimethyl ether, xenon, sulfurhexafluoride, halogenated and partially halogenated materials such aschlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons,perfluorocarbons (such as perfluoromethane and perfluoropropane,chloroform, trichloro-fluoromethane, dichloro-difluoromethane,dichloro-tetrafluoroethane) and mixtures thereof. Preferably, thesupercritical fluid is hexafluoropropane (FC-236EA), or1,1,1,2,3,3-hexafluoropropane. Preferably, the supercritical fluid ishexafluoropropane (FC-236EA), or 1.1, 1.2, 3, 3-hexafluoropropane foruse in PLGA polymer coatings.

“Sintering” as used herein refers to the process by which parts of thepolymer or the entire polymer becomes continuous (e.g., formation of acontinuous polymer film). As discussed herein, the sintering process iscontrolled to produce a fully conformal continuous polymer (completesintering) or to produce regions or domains of continuous coating whileproducing voids (discontinuities) in the polymer. As well, the sinteringprocess is controlled such that some phase separation is obtained ormaintained between polymer different polymers (e.g., polymers A and B)and/or to produce phase separation between discrete polymer particles.Through the sintering process, the adhesions properties of the coatingare improved to reduce flaking of detachment of the coating from thesubstrate during manipulation in use. As described herein, in someembodiments, the sintering process is controlled to provide incompletesintering of the polymer. In embodiments involving incomplete sintering,a polymer is formed with continuous domains, and voids, gaps, cavities,pores, channels or, interstices that provide space for sequestering atherapeutic agent which is released under controlled conditions.Depending on the nature of the polymer, the size of polymer particlesand/or other polymer properties, a compressed gas, a densified gas, anear critical fluid or a super-critical fluid may be employed. In oneexample, carbon dioxide is used to treat a substrate that has beencoated with a polymer and a drug, using dry powder and RESSelectrostatic coating processes. In another example, isobutylene isemployed in the sintering process. In other examples a mixture of carbondioxide and isobutylene is employed. In another example,1,1,2,3,3-hexafluoropropane is employed in the sintering process.

When an amorphous material is heated to a temperature above its glasstransition temperature, or when a crystalline material is heated to atemperature above a phase transition temperature, the moleculescomprising the material are more mobile, which in turn means that theyare more active and thus more prone to reactions such as oxidation.However, when an amorphous material is maintained at a temperature belowits glass transition temperature, its molecules are substantiallyimmobilized and thus less prone to reactions. Likewise, when acrystalline material is maintained at a temperature below its phasetransition temperature, its molecules are substantially immobilized andthus less prone to reactions. Accordingly, processing drug components atmild conditions, such as the deposition and sintering conditionsdescribed herein, minimizes cross-reactions and degradation of the drugcomponent. One type of reaction that is minimized by the processes ofthe invention relates to the ability to avoid conventional solventswhich in turn minimizes—oxidation of drug, whether in amorphous,semi-crystalline, or crystalline form, by reducing exposure thereof tofree radicals, residual solvents, protic materials, polar-proticmaterials, oxidation initiators, and autoxidation initiators.

“Rapid Expansion of Supercritical Solutions” or “RESS” as used hereininvolves the dissolution of a polymer into a compressed fluid, typicallya supercritical fluid, followed by rapid expansion into a chamber atlower pressure, typically near atmospheric conditions. The rapidexpansion of the supercritical fluid solution through a small opening,with its accompanying decrease in density, reduces the dissolutioncapacity of the fluid and results in the nucleation and growth ofpolymer particles. The atmosphere of the chamber is maintained in anelectrically neutral state by maintaining an isolating “cloud” of gas inthe chamber, Carbon dioxide, nitrogen, argon, helium, or otherappropriate gas is employed to prevent electrical charge is transferredfrom the substrate to the surrounding environment.

“Electrostatic Rapid Expansion of Supercritical Solutions” or “e-RESS”or “CRESS” as used herein refers to Electrostatic Capture as describedherein combined with Rapid Expansion of Supercritical Solutions asdescribed herein. In some embodiments, Electrostatic Rapid Expansion ofSupercritical Solutions refers to Electrostatic capture as described inthe art, e.g., in U.S. Pat. No. 6,756,084. “Electrostatic deposition ofparticles generated from rapid expansion of supercritical fluidsolutions,” incorporated herein by reference in its entirety.

Electrostatic Capture may be used for depositing a coating on a device(e.g. a balloon), and may be referred to as “eSTAT” herein. Coating isapplied to the balloons via eSTAT attraction, where the positivelycharged coating coat a negatively charged device. For example, in someembodiments, sirolimus in crystalline form is applied to the balloonsvia eSTAT attraction where the positively charged drug particles coatthe negatively charged balloons. The sirolimus coated on the balloon, insome embodiments, has an inherently positive charge.

FIG. 2 depicts an example eSTAT process for coating 12 angioplastyballoons with sirolimus. In this example process, an eight literaluminum foil coated bell jar 2 is kept in place, but is notelectrically grounded. Milled sirolimus (15.5 mg) is placed in aSwagelok ½″ tee filter 18 (Swagelok, Inc., Supplemental Figure SI 5)connected to a pulsed pneumatic valve 20 (Swagelok, Inc., SupplementalFigure SI 6) attached to a cylinder of compressed nitrogen 22. The teefilter is connected on the other end to the eSTAT nozzle 14, a ½″×⅜″Swagelok reducing union fitted to a modified ⅜″ Swagelok bulkhead union(Swagelok, Inc., Supplemental Figure SI 7) via ½″ (outer diameter)polypropylene tubing 16. Balloon(s) 4 are mounted in place under thebell jar 2. In this example, twelve 3.0 mm width balloons at a time arecoated with the positively charged milled sirolimus 6. The balloons 4may be of various lengths, such as lengths ranging from 17 mm to 23 mm,however, in other embodiments, other sizes may be used. In someembodiments, fewer or more balloons may be coated at a time. Theballoons 4 used during the coating process are typically mounted oncatheters having wires 10 disposed therein 8 which are coupled to a highvoltage power supply 12 (such as a Spellman SL30 high voltage powersupply), which may be set at −15 kV, for example.

In some embodiments, the lengths of the balloons may be any length from5 mm to 35 mm, or any of the following lengths, for example: about 5 mm,about 7 mm, about 8 mm, about 10 mm, about 12 mm, about 13 mm, about 15mm, about 18 mm, about 20 mm, about 21 mm, about 23 mm, about 25 mm,about 28 mm, about 30 mm, about 32 mm, about 33 mm, and about 35 mm. Theterm “about” when used in the context of balloon length, can meanvariations of for example, 10%, 25%, 50%), 0.1 mm, 0.25 mm, 0.5 mm, 1mm, 2 mm, and 5 mm, depending on the embodiment.

In some embodiments, the diameters (i.e. widths) of the balloons may beany diameter from 1.5 mm to 6.0 mm, or any of the following diameters,for example: about 1.5 mm, about 1.8 mm, about 2.0 mm, about 2.25 mm,about 2.5 mm, about 2.75 mm, about 3.0 mm, about 3.25 mm, about 3.5 mm,about 3.75 mm, about 4.0 mm, about 4.25 mm, about 4.5 mm, about 4.75 mm,about 5.0 mm, about 5.25 mm, and about 5.5 mm. The term “about” whenused in the context of balloon diameter (or width), can mean variationsof for example, 10%>, 25%, 50%, 0.1 mm, 0.25 mm, 0.3 mm, 0.4 mm, 0.5 mm,0.75 mm, 1 mm, and 2 mm, depending on the embodiment.

In some embodiments a minimum of one balloon is coated at a time. Insome embodiments, at least one of: at least 3 balloons, at least 5balloons, at least 6 balloons, at least 8 balloons, at least 10balloons, at least 12 balloons, at least 15 balloons, at least 16balloons, at least 20 balloons, at least 24 balloons, and at least 30balloons are coated at a time.

These balloons may or may not be pre-coated with a polymer, such asPLGA. Coating of the balloons may be achieved by various means, such asdip coating, spray coating, or coating using an RESS method. Forexample, a polymer (e.g., PLGA) is applied to the balloons via rapidexpansion of supercritical solutions (RESS), where the solute (e.g.,PLGA) is dissolved in a supercritical fluid then rapidly expanded withsudden decompression by passing through a short nozzle into an area oflow temperature and pressure. These conditions cause the dissolved PLGAto rapidly precipitate as a fine powder with a narrow distribution ofparticle size resulting in a uniform coating on the angioplastyballoons.

FIG. 3 depicts an example RESS process for coating balloons 4 with PLGA.The PLGA is loaded into a vessel 24 in which it is dissolved in HFC236eafrom a HFC236ea cylinder 26 which is sent to the vessel 24 through asyringe pump 28 (for example, an Isco 260D syringe pump). The PLGA thusforms a supercritical solution with the HFC236 ea, which is stirred at ahigh pressure (5500 psi) in mixing view cells (50 cc). The PLGA solutionis sent through a syringe pump 30 (for example, an Isco 260D syringepump) which sends the solution through a heater block 32 (withtemperature control feedback) and then through a timed pneumatic valve34 which is heated at 137 C. The PLGA solution is then sent through acapillary tube 36 (e.g. PEEKsil capillary tube 1/16″ outer diameter by100 micron inner diameter by 10 cm long) which is surrounded by astainless steel sheath (e.g., % inches thick stainless steel sheath).The PLGA is then ejected through a nozzle 40 which is electricallygrounded (for example, via a stainless steel sheath). When the PLGAsolution exits the nozzle 40, the PLGA is ejected as dry PLGA particles42, as the solution comprising PLGA and FIFC236ea rapidly expands. Theballoons 4 used during the coating process are typically mounted oncatheters having wires 10 disposed therein 8 which are electricallygrounded 44. The wires 10 may be coupled to a high voltage power supply12 (such as a Spellman SL30 high voltage power supply), in order tofacilitate the eSTAT coating of the balloons with the active agent,however, during the RESS process described in this embodiment, theballoons are electrically grounded and no current flows from the powersupply 12.

When viewed in combination, FIGS. 2 and 3 indicate a single apparatusthat can both coat according to an RESS process and an eSTAT process.Elements called out and depicted in FIG. 2 may similarly be called outin FIG. 3 , and vice versa. Alternatively, separate coating apparatusesmay be used to separately coat according to an RESS process and an eSTATprocess.

“Solution Enhanced Dispersion of Supercritical Solutions” or “SEDS” asused herein involves a spray process for the generation of polymerparticles, which are formed when a compressed fluid (e.g., supercriticalfluid, preferably supercritical CO₂) is used as a diluent to a vehiclein which a polymer is dissolved (one that can dissolve both the polymerand the compressed fluid). The mixing of the compressed fluid diluentwith the polymer-containing solution may be achieved by encounter of afirst stream containing the polymer solution and a second streamcontaining the diluent compressed fluid, for example, within one spraynozzle or by the use of multiple spray nozzles. The solvent in thepolymer solution may be one compound or a mixture of two or moreingredients and may be or comprise an alcohol (including diols, triols,etc.), ether, amine, ketone, carbonate, or alkanes, or hydrocarbon(aliphatic or aromatic) or may be a mixture of compounds, such asmixtures of alkanes, or mixtures of one or more alkanes in combinationwith additional compounds such as one or more alcohols, (e.g., from 0 or0.1 to 5% of a Ci to Ci₅ alcohol, including diols, triols, etc.). Seefor example U.S. Pat. No. 6,669,785, incorporated herein by reference inits entirety. The solvent may optionally contain a surfactant, as alsodescribed in, e.g., U.S. Pat. No. 6,669,785.

In one embodiment of the SEDS process, a first stream of fluidcomprising a polymer dissolved in a common solvent is co-sprayed with asecond stream of compressed fluid, Polymer particles are produced as thesecond stream acts as a diluent that weakens the solvent in the polymersolution of the first stream. The now combined streams of fluid, alongwith the polymer particles, flow out of the nozzle assembly into acollection vessel. Control of particle size, particle size distribution,and morphology is achieved by tailoring the following process variables:temperature, pressure, solvent composition of the first stream,flow-rate of the first stream, flow-rate of the second stream,composition of the second stream (where soluble additives may be addedto the compressed gas), and conditions of the capture vessel. Typicallythe capture vessel contains a fluid phase that is at least five to tentimes (5-1 Ox) atmospheric pressure.

“Electrostatic Dry Powder Coating” or “e-DPC” or “eDPC” as used hereinrefers to Electrostatic Capture as described herein combined with DryPowder Coating. e-DPC deposits material (including, for example, polymeror impermeable dispersed solid) on the device or other substrate as drypowder, using electrostatic capture to attract the powder particles tothe substrate. Dry powder spraying (“Dry Powder Coating” or “DPC”) iswell known in the art, and dry powder spraying coupled withelectrostatic capture has been described, for example in U.S. Pat. Nos.5,470,603, 6,319,541, and 6,372,246, all incorporated herein byreference in their entirety. Methods for depositing coatings aredescribed, e.g., in WO 2008/148013, “Polymer Films for Medical DeviceCoating,” incorporated herein by reference in its entirety.

“Dipping Process” and “Spraying Process” as used herein refer to methodsof coating substrates that have been described at length in the art.These processes can be used for coating medical devices withpharmaceutical agents. Spray coating, described in, e.g., U.S. Pat. No.7,419,696, “Medical devices for delivering a therapeutic agent andmethod of preparation” and elsewhere herein, can involve spraying orairbrushing a thin layer of solubilized coating or dry powder coatingonto a substrate. Dip coating involves, e.g., dipping a substrate in aliquid, and then removing and drying it. Dip coating is described in,e.g., U.S. Pat. No. 5,837,313 “Drug release stent coating process,”incorporated herein by reference in its entirety.

“Bulk properties” properties of a coating including a pharmaceutical ora biological agent that can be enhanced through the methods of theinvention include for example: adhesion, smoothness, conformality,thickness, and compositional mixing.

“Electrostatically charged” or “electrical potential” or “electrostaticcapture” as used herein refers to the collection of the spray-producedparticles upon a substrate that has a different electrostatic potentialthan the sprayed particles. Thus, the substrate is at an attractiveelectronic potential with respect to the particles exiting, whichresults in the capture of the particles upon the substrate, i.e. thesubstrate and particles are oppositely charged, and the particlestransport through the gaseous medium of the capture vessel onto thesurface of the substrate is enhanced via electrostatic attraction. Thismay be achieved by charging the particles and grounding the substrate orconversely charging the substrate and grounding the particles, bycharging the particles at one potential (e.g., negative charge) andcharging the substrate at an opposite potential (e.g., positive charge),or by some other process, which would be easily envisaged by one ofskill in the art of electrostatic capture.

“Depositing the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess without electrically charging the substrate” as used hereinrefers to any of these processes as performed without intentionallyelectrically charging the substrate. It is understood that the substratemight become electrically charged unintentionally during any of theseprocesses.

“Depositing the active agent by an e-RESS, an c-SEDS, or an e-DPCprocess without creating an electrical potential between the substrateand a coating apparatus” as used herein refers to any of these processesas performed without intentionally generating an electrical potentialbetween the substrate and the coating apparatus. It is understood thatelectrical potential between the substrate and the coating apparatusmight be generated unintentionally during any of these processes.

“Intimate mixture” as used herein, refers to two or more materials,compounds, or substances that are uniformly distributed or dispersedtogether.

“Layer” as used herein refers to a material covering a surface orforming an overlying part or segment. Two different layers may haveoverlapping portions whereby material from one layer may be in contactwith material from another layer. Contact between materials of differentlayers can be measured by determining a distance between the materials.For example, Raman spectroscopy may be employed in identifying materialsfrom two layers present in close proximity to each other.

While layers defined by uniform thickness and/or regular shape arecontemplated herein, several embodiments described herein relate tolayers having varying thickness and/or irregular shape. Material of onelayer may extend into the space largely occupied by material of anotherlayer. For example, in a coating having three layers formed in sequenceas a first polymer layer, a pharmaceutical agent layer and a secondpolymer layer, material from the second polymer layer which is depositedlast in this sequence may extend into the space largely occupied bymaterial of the pharmaceutical agent layer whereby material from thesecond polymer layer may have contact with material from thepharmaceutical layer. It is also contemplated that material from thesecond polymer layer may extend through the entire layer largelyoccupied by pharmaceutical agent and contact material from the firstpolymer layer.

It should be noted however that contact between material from the secondpolymer layer (or the first polymer layer) and material from thepharmaceutical agent layer (e.g.; a pharmaceutical agent crystalparticle or a portion thereof) does not necessarily imply formation of amixture between the material from the first or second polymer layers andmaterial from the pharmaceutical agent layer. In some embodiments, alayer may be defined by the physical three-dimensional space occupied bycrystalline particles of a pharmaceutical agent (and/or biologicalagent). It is contemplated that such layer may or may not be continuousas physical space occupied by the crystal particles of pharmaceuticalagents may be interrupted, for example, by polymer material from anadjacent polymer layer. An adjacent polymer layer may be a layer that isin physical proximity to be pharmaceutical agent particles in thepharmaceutical agent layer. Similarly, an adjacent layer may be thelayer formed in a process step right before or right after the processstep in which pharmaceutical agent particles are deposited to form thepharmaceutical agent layer.

As described herein, material deposition and layer formation providedherein are advantageous in that the pharmaceutical agent remains largelyin crystalline form during the entire process. While the polymerparticles and the pharmaceutical agent particles may be in contact, thelayer formation process is controlled to avoid formation of a mixturebetween the pharmaceutical agent particles the polymer particles duringformation of a coated device.

In some embodiments, the coating comprises a plurality of layersdeposited on the substrate, wherein at least one of the layers comprisesthe active agent. In some embodiments, at least one of the layerscomprises a polymer. In some embodiments, the polymer is bioabsorbable.In some embodiments, the active agent and the polymer are in the samelayer, in separate layers, or form overlapping layers. In someembodiments, the plurality of layers comprise five layers deposited asfollows: a first polymer layer, a first active agent layer, a secondpolymer layer, a second active agent layer and a third polymer layer.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a plurality of layers deposited on the substrate,wherein at least one of the layers comprises the active agent. In someembodiments, at least one of the layers comprises a polymer. In someembodiments, the polymer is bioabsorbable. In some embodiments, theactive agent and the polymer are in the same layer, in separate layers,or form overlapping layers. In some embodiments, the coating comprises aplurality of layers deposited on the substrate, wherein at least one ofthe layers comprises the pharmaceutical agent. In some embodiments, thepharmaceutical agent and the polymer are in the same layer, in separatelayers, or form overlapping layers. In some embodiments, the pluralityof layers comprise five layers deposited as follows: a first polymerlayer, a first active agent layer, a second polymer layer, a secondactive agent layer and a third polymer layer. In some embodiments, theplurality of layers comprise five layers deposited as follows: a firstpolymer layer, a first pharmaceutical agent layer, a second polymerlayer, a second pharmaceutical agent layer and a third polymer layer. Insome embodiments, the plurality of layers comprise five layers depositedas follows: a first polymer layer, a first active biological agentlayer, a second polymer layer, a second active biological agent layerand a third polymer layer.

In some embodiments, the device provides the coating to the interventionsite over an area of delivery greater than the outer surface contactarea of the substrate. In some embodiments, the area of delivery is atleast 110% greater than the outer surface contact area of the substrate.In some embodiments, the area of delivery is at least 110% to 200%greater than the outer surface contact area of the substrate. In someembodiments, the area of delivery is at least 200%> greater than theouter surface contact area of the substrate.

“Laminate coating” as used herein refers to a coating made up of two ormore layers of material. Means for creating a laminate coating asdescribed herein (e.g.; a laminate coating comprising bioabsorbablepolymer(s) and pharmaceutical agent) may include coating the stent withdrug and polymer as described herein (e-RESS, e-DPC, compressed-gassintering). The process comprises performing multiple and sequentialcoating steps (with sintering steps for polymer materials) whereindifferent materials may be deposited in each step, thus creating alaminated structure with a multitude of layers (at least 2 layers)including polymer layers and pharmaceutical agent layers to build thefinal device (e.g.; laminate coated stent).

“Portion of the coating” and “portion of the active agent” as usedherein refer to an amount or percentage of the coating or active agentthat is freed, dissociated, and/or transferred from the substrate to theintervention site, either at a designated point in delivery, during acertain period of delivery, or in total throughout the entire deliveryprocess. In embodiments, the device and methods of the invention areadapted to free, dissociate, and/or transfer a certain amount of thecoating and/or active agent.

For example, in embodiments, at least about 10%, at least about 20%, atleast about 30%), at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating is adapted to be freed, dissociated, and/or to betransferred from the substrate to the intervention site. In embodiments,at least about 10%, at least about 20%, at least about 30%, at leastabout 50%, at least about 75%, at least about 85%, at least about 90%,at least about 95%), and/or at least about 99% of the active agent isadapted to be freed, dissociated, and/or to be transferred from thesubstrate to the intervention site.

The portion of the coating and/or that is freed, dissociated, ortransferred from the device substrate is influenced by any or acombination of, e.g., the size, shape, and flexibility of the devicesubstrate, the size, shape, surface qualities of and conditions (e.g.,blood or lymph circulation, temperature, etc.) at the intervention site,the composition of the coating, including the particular active agent(s)and specific polymer component(s) used in the coating, the relativeproportions of these components, the use of any release agent(s), andsubstrate characteristics. Any one or more of these and other aspects ofthe device and methods of the invention can be adapted to influence theportion of the coating and/or active agent freed, dissociated, and/ortransferred, as desired to produce the desired clinical outcome.

“Substantially all of the coating” as used herein refers to at leastabout 50%, at least about 75%) at least about 85%, at least about 90%,at least about 95%, at least about 97%, and/or at least about 99%percent of the coating that was present on the device prior to use.

“At least a portion of the substrate” as used herein refers to an amountand/or percentage of the substrate. In embodiments of the device andmethods of the invention wherein a coating is on “at least a portion ofthe substrate,” at least about 10%, at least about 20%, at least about30%), at least about 50%, at least about 75%, at least about 85%, atleast about 90%, at least about 95%, and/or at least about 99% of thesubstrate is coated. In embodiments wherein “at least a portion of thesubstrate” is bioabsorbable, at least about 10%, at least about 20%, atleast about 30%, at least about 50%), at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%)of the substrate is bioabsorbable.

“Transferring at least a portion” as used herein in the context oftransferring a coating or active agent from the substrate to anintervention site refers to an amount and/or percentage of the coatingor active agent that is transferred from the substrate to anintervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating or active agent istransferred from the substrate to an intervention site, at least about10%, at least about 20%, at least about 30%), at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%), and/or at least about 99% of the coating or active agent istransferred from the substrate to the intervention site. In someembodiments, at least about 10%, at least about 20%, at least about 30%,at least about 50%, at least about 75%, at least about 85%, at leastabout 90%, at least about 95%, and/or at least about 99% of the coatingis adapted to transfer from the substrate to the intervention site. Insome embodiments, at least about 10% of the coating is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 20%> of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 30%> of the coating is adapted to transfer from thesubstrate to the intervention site. In some embodiments, at least about50%> of the coating is adapted to transfer from the substrate to theintervention site. In some embodiments, at least about 75%) of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 85% of the coating is adaptedto transfer from the substrate to the intervention site. In someembodiments, at least about 90%> of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 95% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 99% of thecoating is adapted to transfer from the substrate to the interventionsite. As used herein, “about” when used in reference to a percentage ofthe coating can mean ranges of 1%>-5%>, of 5%-10%, of 10%-20%, and/or of10%-50% (as a percent of the percentage of the coating transferred, oras a variation of the percentage of the coating transferred).

In some embodiments, the coating portion that is adapted to transferupon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, device is adapted to transferless than about 1%, less than about 5%, less than about 10%, less thanabout 15%, less than about 25%, less than about 50%, less than about70%, less than about 80%, and/or less than about 90%) of the coatingabsent stimulation of the coating.

In some embodiments, at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of theactive agent is adapted to transfer from the substrate to theintervention site. In some embodiments, at least about 10% of the activeagent is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 20% of the active agent isadapted to transfer from the substrate to the intervention site. In someembodiments, at least about 30% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 50%) of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 75% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 85% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 90% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 95%) of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 99% of the active agent is adapted totransfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the active agent canmean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 0%-50% (as apercent of the percentage of the active agent transferred, or as avariation of the percentage of the active agent transferred).

In some embodiments, the active agent portion that is adapted totransfer upon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, the device is adapted totransfer less than about 1%>, less than about 5%>, less than about 10%>,less than about 15%), less than about 25%>, less than about 50%>, lessthan about 70%>, less than about 80%>, and/or less than about 90%> ofthe active agent absent stimulation of the coating.

In some embodiments, the device is adapted to transfer at least about10%>, at least about 20%), at least about 30%>, at least about 50%>, atleast about 75%>, at least about 85%>, at least about 90%), at leastabout 95%>, and/or at least about 99%> of the coating from the substrateto the intervention site. In some embodiments, the device is adapted totransfer at least about 10%> of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 20%) of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 30%> of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 50%> of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 75%> of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 85%> of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 90%> of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 95%> of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 99%> of the coating from the substrate to theintervention site. As used herein, “about” when used in reference to apercentage of the coating can mean ranges of 1%>-5%>, of 5%>-10%>, of10%-20%), and/or of 10%>-50%> (as a percent of the percentage of thecoating transferred, or as a variation of the percentage of the coatingtransferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%>, lessthan about 5%>, less than about 10%>, less than about 15%>, less thanabout 25%>, less than about 50%>, less than about 70%>, less than about80%>, and/or less than about 90%> of the coating absent stimulation ofthe coating.

In some embodiments, the device is adapted to transfer at least about10%>, at least about 20%), at least about 30%>, at least about 50%>, atleast about 75%>, at least about 85%>, at least about 90%), at leastabout 95%>, and/or at least about 99%> of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 10% of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 20%> of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 30%> of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 50%> of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 75% of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 85% of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 90% of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 95% of the active agent from thesubstrate to the intervention site. In some embodiments, the device isadapted to transfer at least about 99% of the active agent from thesubstrate to the intervention site. As used herein, “about” when used inreference to a percentage of the active agent can mean ranges of 1%-5%,of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percent of the percentageof the active agent transferred, or as a variation of the percentage ofthe active agent transferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, the stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%, less than about 15%, less than about25%), less than about 50%, less than about 70%, less than about 80%,less than about 90% of the active agent absent stimulation of thecoating.

“Freeing at least a portion” as used herein in the context of freeing acoating and/or active agent from the substrate at an intervention siterefers to an amount and/or percentage of a coating or active agent thatis freed from the substrate at an intervention site. In embodiments ofthe device and methods of the invention wherein at least a portion of acoating or active agent is freed from the substrate at an interventionsite, at least about 10%, at least about 20%, at least about 30%, atleast about 50%), at least about 75%, at least about 85%, at least about90%, at least about 95%, and/or at least about 99% of the coating oractive agent is freed from the substrate at the intervention site. Insome embodiments, the device is adapted to free at least about 10%, atleast about 20%, at least about 30%), at least about 50%, at least about75%, at least about 85%, at least about 90%, at least about 95%, and/orat least about 99% of the coating from the substrate. In someembodiments, the device is adapted to free at least about 10% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 20% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 30% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 50% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 75% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 85% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 90%> of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 95% o of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 99% of thecoating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%>-5%>, of 5%>-10%>, of 10%)-20%), and/or of 10%-50% (as apercent of the percentage of the coating freed, or as a variation of thepercentage of the coating freed).

In some embodiments, the coating portion that frees upon stimulation ison at least one of a distal surface of the substrate, a middle surfaceof the substrate, a proximal surface of the substrate, and an abluminalsurface of the substrate.

In some embodiments, the stimulation decreases the contact between thecoating and the substrate. In some embodiments, the device is adapted tofree less than about 1%, less than about 5% o, less than about 10%, lessthan about 15%, less than about 25%, less than about 50%, less thanabout 70%), less than about 80%, less than about 90% of the coatingabsent stimulation of the coating.

“Dissociating at least a portion” as used herein in the context ofdissociating a coating and/or active agent from the substrate at anintervention site refers to an amount and/or percentage of a coatingand/or active agent that is dissociated from the substrate at anintervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdissociated from the substrate at an intervention site, at least about10%, at least about 20%), at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating and/or active agent isdissociated from the substrate at the intervention site.

In some embodiments, the device is adapted to dissociate at least about10%, at least about 20%), at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%), at least about95%, and/or at least about 99% of the coating from the substrate. Insome embodiments, the device is adapted to dissociate at least about 10%of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 20% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 30% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 50% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 75% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 85% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 90% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 95% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 99% ofthe coating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%>-5%>, of 5%>-10%>, of 10%)-20%), and/or of 10%-50% (as apercent of the percentage of the coating dissociated, or as a variationof the percentage of the coating dissociated).

In some embodiments, the coating portion that dissociates uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments,stimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to dissociate less than about1%, less than about 5%, less than about 10%, less than about 15%, lessthan about 25% o, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

“Depositing at least a portion” as used herein in the context of acoating and/or active agent at an intervention site refers to an amountand/or percentage of a coating and/or active agent that is deposited atan intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdeposited at an intervention site, at least about 10%, at least about20%, at least about 30%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating and/or active agent is deposited at theintervention site. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,depositing deposits less than about 1%, less than about 5%), less thanabout 10%, less than about 15%, less than about 25%, less than about50%, less than about 70%, less than about 80%, and/or less than about90% of the coating absent stimulating at least one of the coating andthe substrate.

“Delivering at least a portion” as used herein in the context of acoating and/or active agent at an intervention site refers to an amountand/or percentage of a coating and/or active agent that is delivered toan intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdelivered to an intervention site, at least about 10%, at least about20%, at least about 30%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating and/or active agent is delivered to theintervention site.

In some embodiments, the device is adapted to deliver at least about10%, at least about 20%), at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating to the intervention site.In some embodiments, the device is adapted to deliver at least about 10%of the coating to the intervention site. In some embodiments, the deviceis adapted to deliver at least about 20% of the coating to theintervention site. In some embodiments, the device is adapted to deliverat least about 30% of the coating to the intervention site. In someembodiments, the device is adapted to deliver at least about 50% of thecoating to the intervention site. In some embodiments, the device isadapted to deliver at least about 75% of the coating to the interventionsite. In some embodiments, the device is adapted to deliver at leastabout 85% of the coating to the intervention site. In some embodiments,the device is adapted to deliver at least about 90% of the coating tothe intervention site. In some embodiments, the device is adapted todeliver at least about 95% of the coating to the intervention site. Insome embodiments, the device is adapted to deliver at least about 99% ofthe coating to the intervention site. As used herein, “about” when usedin reference to a percentage of the coating can mean ranges of 1%-5%, of5%-10%, of 10%-20%, and/or of 10%-50% (as a percent of the percentage ofthe coating delivered, or as a variation of the percentage of thecoating delivered).

In some embodiments, the coating portion that is delivered uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments, thestimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to deliver less than about1%, less than about 5%, less than about 10%, less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, depositing at least a portion of the coatingcomprises depositing at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of thecoating at the intervention site. In some embodiments, stimulatingdecreases the contact between the coating and the substrate. In someembodiments, depositing deposits less than about 1%, less than about 5%,less than about 10%), less than about 15%, less than about 25%, lessthan about 50%, less than about 70%, less than about 80%, and/or lessthan about 90% of the coating absent stimulating at least one of thecoating and the substrate.

“Tacking at least a portion” as used herein in the context of tacking atleast a portion of the coating to an intervention site refers to anamount and/or percentage of a coating and/or active agent that is tackedat an intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent istacked at an intervention site, at least about 10%), at least about 20%,at least about 30%, at least about 50%, at least about 75%, at leastabout 85%, at least about 90%, at least about 95%, and/or at least about99% of the coating and/or active agent is tacked at the interventionsite. In some embodiments, stimulating decreases the contact between thecoating and the substrate. In some embodiments, tacking tacks less thanabout 1%, less than about 5%, less than about 10%, less than about 15%,less than about 25%, less than about 50%, less than about 70%), lessthan about 80%, and/or less than about 90% of the coating absentstimulating at least one of the coating and the substrate. In someembodiments, the device comprises a tacking element that cooperates withthe stimulation to tack the coating to the intervention site. In someembodiments, the device comprises a tacking element that tacks thecoating to the substrate until stimulating with a stimulation.

“Adhere,” “adherence,” “adhered,” “cohere,” “coherence,” “cohered,” andrelated terms, as used herein in the context of adherence or coherenceof the substrate to the coating refer to an interaction between thesubstrate and the coating that is sufficiently strong to maintain theassociation of the coating with the substrate for an amount of timeprior to the stimulation, e.g., mechanical, chemical, thermal,electromagnetic, or some stimulation, that is intended to cause thecoating to be freed, dissociated, and/or transferred. These same terms,as used in the context of an interaction between the coating and thetarget tissue area and/or intervention site refer to an interactionbetween the coating and the target tissue area and/or intervention sitethat is sufficient to keep the coating associated with the target tissuearea and/or intervention site for an amount of time as desired fortreatment, e.g., at least about 12 hours, about 1 day, about 3 days,about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks,about 45 days, about 60 days, about 90 days, about 180 days, about 6months, about 9 months, about 1 year, about 1 to about 2 days, about 1to about 5 days, about 1 to about 2 weeks, about 2 to about 4 weeks,about 45 to about 60 days, about 45 to about 90 days, about 30 to about90 days, about 60 to about 90 days, about 90 to about 180 days, about 60to about 180 days, about 180 to about 365 days, about 6 months to about9 months, about 9 months to about 12 months, about 9 months to about 15months, and about 1 year to about 2 years.

“Balloon” as used herein refers to a flexible sac that can be inflatedwithin a natural or non-natural body lumen or cavity, or used to createa cavity, or used to enlarge an existing cavity. The balloon can be usedtransiently to dilate a lumen or cavity and thereafter may be deflatedand/or removed from the subject during the medical procedure orthereafter. In embodiments, the balloon can be expanded within the bodyand has a coating thereon that is freed (at least in part) from theballoon and left behind in the lumen or cavity when the balloon isremoved. A coating can be applied to a balloon either after the balloonhas been compacted for insertion, resulting in a coating that partiallycovers the surface of the balloon, or it can be applied prior to orduring compaction. In embodiments, a coating is applied to the balloonboth prior to and after compaction of the balloon. In embodiments, theballoon is compacted by, e.g., crimping or folding. Methods ofcompacting balloons have been described, e.g., in U.S. Pat. No.7,308,748, “Method for compressing an intraluminal device,” and U.S.Pat. No. 7,152,452. “Assembly for crimping an intraluminal device andmethod of use,” relating to uniformly crimping a balloon onto a catheteror other intraluminal device, and U.S. Pat. No. 5,350,361 “Tri-foldballoon for dilatation catheter and related method,” relating to balloonfolding methods and devices, all incorporated herein by reference intheir entirety. In some embodiments the balloon is delivered to theintervention site by a delivery device. In some embodiments, thedelivery device comprises catheter. In some embodiments, the balloon isan angioplasty balloon. Balloons can be delivered, removed, andvisualized during delivery and removal by methods known in the art,e.g., for inserting angioplasty balloons, stents, and other medicaldevices. Methods for visualizing a treatment area and planninginstrument insertion are described, e.g., in U.S. Pat. No. 7,171,255,“Virtual reality 3D visualization for surgical procedures” and U.S. Pat.No. 6,610,013, “3D ultrasound-guided intraoperative prostatebrachytherapy,” incorporated herein by reference in their entirety.

“Compliant balloon” as used herein refers to a balloon which conforms tothe intervention site relatively more than a semi-compliant balloon andstill more so than a non-compliant balloon. Compliant balloons expandand stretch with increasing pressure within the balloon, and are madefrom such materials as polyethylene or polyolefin copolymers. There isin the art a general classification of balloons based on theirexpandability or “compliance” relative to each other, as described e.g.,in U.S. Pat. No. 5,556,383. “Block copolymer elastomer catheterballoons.” Generally, “non-compliant” balloons are the least elastic,increasing in diameter about 2-7%, typically about 5%, as the balloon ispressurized from an inflation pressure of about 6 atm to a pressure ofabout 12 atm, that is, they have a “distension” over that pressure rangeof about 5%. “Semi-compliant” balloons have somewhat greaterdistensions, generally 7-16% and typically 10-12% over the samepressurization range. “Compliant” balloons are still more distensible,having distensions generally in the range of 16-40%) and typically about21%> over the same pressure range. Maximum distensions, i.e. distensionfrom nominal diameter to burst, of various balloon materials may besignificantly higher than the distension percentages discussed abovebecause wall strengths, and thus burst pressures, vary widely betweenballoon materials. These distension ranges are intended to providegeneral guidance, as one of skill in the art will be aware that thecompliance of a balloon is dependent on the dimensions and/orcharacteristics of the cavity and/or lumen walls, not only theexpandability of the balloon.

A compliant balloon may be used in the vasculature of a subject. Acompliant balloon might also be used in any tube or hole outside thevasculature (whether naturally occurring or man-made, or created duringan injury). For a non-limiting example, a compliant balloon might beused in a lumpectomy to put a coating at the site where a tumor wasremoved, to: treat an abscess, treat an infection, prevent an infection,aid healing, promote healing, or for a combination of any of thesepurposes. The coating in this embodiment may comprise a growth factor.

“Non-Compliant balloon” as used herein refers to a balloon that does notconform to the intervention site, but rather, tends to cause theintervention site to conform to the balloon shape. Non-compliantballoons, commonly made from such materials as polyethyleneterephthalate (PET) or polyamides, remain at a preselected diameter asthe internal balloon pressure increases beyond that required to fullyinflate the balloon. Non-compliant balloons are often used to dilatespaces, e.g., vascular lumens. As noted with respect to a compliantballoon, one of skill in the art will be aware that the compliance of aballoon is dependent on the dimensions and/or characteristics of thecavity and/or lumen walls, not only the expandability of the balloon.

“Cutting balloon” as used herein refers to a balloon commonly used inangioplasty having a special balloon tip with cutting elements, e.g.,small blades, wires, etc. The cutting elements can be activated when theballoon is inflated. In angioplasty procedures, small blades can be usedscore the plaque and the balloon used to compress the fatty matteragainst the vessel wall. A cutting balloon might have tacks or otherwire elements which in some embodiments aid in freeing the coating fromthe balloon, and in some embodiments, may promote adherence or partialadherence of the coating to the target tissue area, or some combinationthereof. In some embodiments, the cutting balloon cutting elements alsoscore the target tissue to promote the coating's introduction into thetarget tissue. In some embodiments, the cutting elements do not cuttissue at the intervention site. In some embodiments, the cuttingballoon comprises tacking elements as the cutting elements.

“Inflation pressure” as used herein refers to the pressure at which aballoon is inflated. As used herein the nominal inflation pressurerefers to the pressure at which a balloon is inflated in order toachieve a particular balloon dimension, usually a diameter of theballoon as designed. The “rated burst pressure” or “RBP” as used hereinrefers to the maximum statistically guaranteed pressure to which aballoon can be inflated without failing. For PTCA and PTA catheters, therated burst pressure is based on the results of in vitro testing to thePTCA and/or PTA catheters, and normally means that at least 99.9% of theballoons tested (with 95% confidence) will not burst at or below thispressure.

“Tacking element” as used herein refers to an element on the substratesurface that is used to influence transfer of the coating to theintervention site. For example, the tacking element can comprise aprojection, e.g., a bump or a spike, on the surface of the substrate. Inembodiments, the tacking element is adapted to secure the coating to thecutting balloon until inflation of the cutting balloon. In someembodiments, tacking element can comprise a wire, and the wire can beshaped in the form of an outward pointing wedge. In certain embodiments,the tacking element does not cut tissue at the intervention site.

As used herein, a “surgical tool” refers to any tool used in a surgicalprocedure. Examples of surgical tools include, but are not limited to:As used herein, a “surgical tool” refers to any tool used in a surgicalprocedure. Examples of surgical tools include, but are not limited to: aknife, a scalpel, a guidewire, a guiding catheter, a introductioncatheter, a distracter, a needle, a syringe, a biopsy device, anarticulator, a Galotti articulator, a bone chisel, a bone crusher, acottle cartilage crusher, a bone cutter, a bone distractor, an Ilizarovapparatus, an intramedullary kinetic bone distractor, a bone drill, abone extender, a bone file, a bone lever, a bone mallet, a bone rasp, abone saw, a bone skid, a bone splint, a bone button, a caliper, acannula, a catheter, a cautery, a clamp, a coagulator, a curette, adepressor, a dilator, a dissecting knife, a distractor, a dermatome,forceps, dissecting forceps, tissue forceps, sponge forceps, boneforceps, Carmalt forceps, Cushing forceps, Dandy forceps, DeBakeyforceps, Doyen intestinal forceps, epilation forceps, Halstead forceps,Kelly forceps, Kocher forceps, mosquito forceps, a hemostat, a hook, anerve hook, an obstetrical hook, a skin hook, a hypodermic needle, alancet, a luxator, a lythotome, a lythotript, a mallet, a partschmallet, a mouth prop, a mouth gag, a mammotome, a needle holder, anoccluder, an osteotome, an Epker osteotome, a periosteal elevator, aJoseph elevator, a Molt periosteal elevator, an Obweg periostealelevator, a septum elevator, a Tessier periosteal elevator, a probe, aretractor, a Senn retractor, a Gelpi retractor, a Weitlaner retractor, aUSA-Army/Navy retractor, an O'Connor-O'Sullivan retractor, a Deaverretractor, a Bookwalter retractor, a Sweetheart retractor, a Joseph skinhook, a Lahey retractor, a Blair (Rollet) retractor, a rigid rakeretractor, a flexible rake retractor, a Ragnell retractor, aLinde-Ragnell retractor, a Davis retractor, a Volkman retractor, aMathieu retractor, a Jackson tracheal hook, a Crile retractor, aMeyerding finger retractor, a Little retractor, a Love Nerve retractor,a Green retractor, a Goelet retractor, a Cushing vein retractor, aLangenbeck retractor, a Richardson retractor, a Richardson-Eastmannretractor, a Kelly retractor, a Parker retractor, a Parker-Mottretractor, a Roux retractor, a Mayo-Collins retractor, a Ribbonretractor, an Aim retractor, a self retaining retractor, a Weitlanerretractor, a Beckman-Weitlaner retractor, a Beckman-Eaton retractor, aBeckman retractor, an Adson retractor, a rib spreader, a rongeur, ascalpel, an ultrasonic scalpel, a laser scalpel, scissors, irisscissors, Kiene scissors, Metzenbaum scissors, Mayo scissors, Tenotomyscissors, a spatula, a speculum, a mouth speculum, a rectal speculum,Sim's vaginal speculum, Cusco's vaginal speculum, a sternal saw, asuction tube, a surgical elevator, a surgical hook, a surgical knife,surgical mesh, a surgical needle, a surgical snare, a surgical sponge, asurgical spoon, a surgical stapler, a suture, a syringe, a tonguedepressor, a tonsillotome, a tooth extractor, a towel clamp, towelforceps, Backhaus towel forceps, Lorna towel forceps, a tracheotome, atissue expander, a subcutaneous inflatable balloon expander, a trephine,a trocar, tweezers, and a venous clipping. In some embodiments, asurgical tool may also and/or alternatively be referred to as a tool forperforming a medical procedure. In some embodiments, a surgical tool mayalso and/or alternatively be a tool for delivering to the interventionsite a biomedical implant.

“Stimulation” as used herein refers to any mechanical stimulation,chemical stimulation, thermal stimulation, electromagnetic stimulation,and/or some stimulation that influences, causes, initiates, and/orresults in the freeing, dissociation, and/or the transfer of the coatingand/or active agent from the substrate.

“Mechanical Stimulation” as used herein refers to use of a mechanicalforce that influences the freeing, dissociation, and/or transfer of thecoating and/or the active agent from the substrate. For example,mechanical stimulation can comprise a shearing force, a compressiveforce, a force exerted on the coating from a substrate side of thecoating, a force exerted on the coating by the substrate, a forceexerted on the coating by an external element, a translation, arotation, a vibration, or a combination thereof. In embodiments, themechanical stimulation comprises balloon expansion, stent expansion,etc. In embodiments, the mechanical stimulation is adapted to augmentthe freeing, dissociation and/or transfer of the coating from thesubstrate. In embodiments, the mechanical stimulation is adapted toinitiate the freeing, dissociation and/or transfer of the coating fromthe substrate. In embodiments, the mechanical stimulation can be adaptedto cause the freeing, dissociation and/or transference of the coatingfrom the substrate. In embodiments, an external element is a part of thesubject. In embodiments, the external element is not part of the device.In embodiments the external element comprises a liquid, e.g., saline orwater. In certain embodiments the liquid is forced between the coatingand the substrate. In embodiments, the mechanical stimulation comprisesa geometric configuration of the substrate that maximizes a shear forceon the coating.

“Chemical Stimulation” as used herein refers to use of a chemical forceto influence the freeing, dissociation, and/or transfer of the coatingfrom the substrate. For example, chemical stimulation can comprise bulkdegradation, interaction with a bodily fluid, interaction with a bodilytissue, a chemical interaction with a non-bodily fluid, a chemicalinteraction with a chemical, an acid-base reaction, an enzymaticreaction, hydrolysis, or a combination thereof. In embodiments, thechemical stimulation is adapted to augment the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is adapted to initiate the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is adapted to cause the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is achieved through the use of a coating thatcomprises a material that is adapted to transfer, free, and/ordissociate from the substrate when at the intervention site in responseto an in-situ enzymatic reaction resulting in a weak bond between thecoating and the substrate.

“Thermal Stimulation” as used herein refers to use of a thermal stimulusto influence the freeing, dissociation, and/or transfer of the coatingfrom the substrate. For example, thermal stimulation can comprise atleast one of a hot stimulus and a cold stimulus. In embodiments, thermalstimulation comprises at least one of a hot stimulus and a cold stimulusadapted to augment the freeing, dissociation and/or transference of thecoating from the substrate. In embodiments, thermal stimulationcomprises at least one of a hot stimulus and a cold stimulus adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In embodiments, thermal stimulation comprises atleast one of a hot stimulus and a cold stimulus adapted to cause thefreeing, dissociation and/or transference of the coating from thesubstrate.

“Electromagnetic Stimulation” as used herein refers to use of anelectromagnetic stimulus to influence the freeing, dissociation, and/ortransfer of the coating from the substrate. For example, theelectromagnetic stimulation is an electromagnetic wave comprising atleast one of, e.g., a radio wave, a micro wave, a infrared wave, nearinfrared wave, a visible light wave, an ultraviolet wave, a X-ray wave,and a gamma wave. In embodiments, the electromagnetic stimulation isadapted to augment the freeing, dissociation and/or transference of thecoating from the substrate. In embodiments, the electromagneticstimulation is adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate. In embodiments, theelectromagnetic stimulation is adapted to cause the freeing,dissociation and/or transference of the coating from the substrate.

“Some Stimulation” as used herein refers to use of a some stimulus toinfluence the freeing, dissociation, and/or transfer of the coating fromthe substrate. For example, some stimulation can comprise a sound wave,wherein the sound wave is at least one of an ultrasound wave, anacoustic sound wave, and an infrasound wave. In embodiments, the somestimulation is adapted to augment the freeing, dissociation and/ortransfer of the coating from the substrate. In embodiments, the somestimulation is adapted to initiate the freeing, dissociation and/ortransfer of the coating from the substrate. In embodiments, the somestimulation is adapted to cause the freeing, dissociation and/ortransfer of the coating from the substrate.

“Release Agent” as used herein refers to a substance or substratestructure that influences the ease, rate, or extent, of release of thecoating from the substrate. In certain embodiments wherein the device isadapted to transfer a portion of the coating and/or active agent fromthe substrate to the intervention site, the device can be so adapted by,e.g., substrate attributes and/or surface modification of the substrate(for non-limiting example: substrate composition, substrate materials,substrate shape, substrate deployment attributes, substrate deliveryattributes, substrate pattern, and/or substrate texture), the deliverysystem of the substrate and coating (for non-limiting example: controlover the substrate, control over the coating using the delivery system,the type of delivery system provided, the materials of the deliverysystem, and/or combinations thereof), coating attributes and/or physicalcharacteristics of the coating (for non-limiting example: selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute), release agent attributes (for non-limitingexample: through the selection a particular release agent and/or themanner in which the release agent is employed to transfer the coatingand/or the active agent, and/or the amount of the release agent used),and/or a combination thereof. Release agents may include biocompatiblerelease agents, non-biocompatible release agents to aggravate and/orotherwise induce a healing response or induce inflammation, powderrelease agents, lubricants (e.g. ePTFE, sugars, other known lubricants),micronized drugs as the release agent (to create a burst layer after thecoating is freed from the substrate, physical release agents (patterningof the substrate to free the coating, others), and/or agents that changeproperties upon insertion (e.g. gels, lipid films, vitamin E, oil,mucosal adhesives, adherent hydrogels, etc.). Methods of patterning asubstrate are described, e.g., in U.S. Pat. No. 7,537,610, “Method andsystem for creating a textured surface on an implantable medicaldevice.” In embodiments, more than one release agent is used, forexample, the substrate can be patterned and also lubricated. In someembodiments, the release agent comprises a viscous fluid.

In some embodiments, the release agent comprises a viscous fluid. Insome embodiments, the viscous fluid comprises oil. In some embodiments,the viscous fluid is a fluid that is viscous relative to water. In someembodiments, the viscous fluid is a fluid that is viscous relative toblood. In some embodiments, the viscous fluid is a fluid that is viscousrelative to urine. In some embodiments, the viscous fluid is a fluidthat is viscous relative to bile. In some embodiments, the viscous fluidis a fluid that is viscous relative to synovial fluid. In someembodiments, the viscous fluid is a fluid that is viscous relative tosaline. In some embodiments, the viscous fluid is a fluid that isviscous relative to a bodily fluid at the intervention site.

In some embodiments, the release agent comprises a physicalcharacteristic of the substrate. In some embodiments, the physicalcharacteristic of the substrate comprises at least one of a patternedcoating surface and a ribbed coating surface. In some embodiments, thepatterned coating surface comprises a stent framework. In someembodiments, the ribbed coating surface comprises an undulatingsubstrate surface. In some embodiments, the ribbed coating surfacecomprises an substrate surface having bumps thereon.

In some embodiments, the release agent comprises a physicalcharacteristic of the coating. In some embodiments, the physicalcharacteristic of the coating comprises a pattern. In some embodiments,the pattern is a textured surface on the substrate side of the coating,wherein the substrate side of the coating is the part of the coating onthe substrate. In some embodiments, the pattern is a textured surface onthe intervention site side of the coating, wherein the intervention siteside of the coating is the part of the coating that is transferred to,and/or delivered to, and/or deposited at the intervention site.

“Extrusion” and/or “Extruded” and/or to “Extrude” as used herein refersto the movement of a substance away from another substance or object,especially upon stimulation, e.g., by a mechanical force. For example,in embodiments of the invention, the coating is extruded from thesubstrate.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to free from the substrate uponstimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to dissociate from the substrate uponstimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises anactive agent, wherein the coating is patterned, and wherein at least aportion of the coating is adapted to transfer from the substrate to anintervention site upon stimulation of the coating.

In some embodiments, the patterned coating comprises at least twodifferent shapes.

“Patterned” as used herein in reference to the coating refers to acoating having at least two different shapes. The shapes can be formedby various methods, including for example, etching, masking,electrostatic capture, and/or by the coating methods described herein.For example the coating may have voids that are at least partiallythrough the thickness of the coating. In some embodiments, the voidsextend fully through the coating. The voids may be in a regularconfiguration, or irregular in shape. The voids may form a repeatingconfiguration to form the patterned coating. The voids may have beenremoved from a smooth or solid coating to form a patterned coating. Thecoating may in some embodiments be patterned by having a surface that isribbed, wavy or bumpy. The coating may in some embodiments be patternedby having been cut and/or etched from a coating sheath and/or sheet in aparticular design. The sheath and/or sheet in such embodiments may havebeen formed using the coating methods for manufacture as describedherein. The pattern design may be chosen to improve the freeing,transfer, and/or dissociation from the substrate. The pattern design maybe chosen to improve the transfer and/or delivery to the interventionsite.

Patterned coatings may be created using the methods and processesdescribed herein, for non-limiting example, by providing a substratehaving a patterned design thereon comprising, for example, a materialthat is chosen to selectively capture the coating particles (whetheractive agent, polymer, or other coating particles) to coat only adesired portion of the substrate. This portion that is coated may be thepatterned design of the substrate.

The term “image enhanced polymer” or “imaging agent” as used hereinrefer to an agent that can be used with the devices and methods of theinvention to view at least one component of the coating, either whilethe coating is on the substrate or after it is freed, dissociated and/ortransferred. In embodiments, an image enhanced polymer serves as atracer, allowing the movement or location of the coated device to beidentified, e.g., using an imaging system. In other embodiments, animage enhanced polymer allows the practitioner to monitor the deliveryand movement of a coating component. In embodiments, use of an imageenhanced polymer enables the practitioner to determine the dose of acomponent of the coating (e.g., the active agent) that is freed,dissociated and/or transferred. Information provided by the imageenhanced polymer or imaging agent about the amount of coatingtransferred to the intervention site can allow the practitioner todetermine the rate at which the coating will be released, therebyallowing prediction of dosing over time. Imaging agents may comprisebarium compounds such as, for non-limiting example, barium sulfate.Imaging agents may comprise iodine compounds. Imaging agents maycomprise any compound that improves radiopacity.

In embodiments, an image enhanced polymer is used with the device andmethods of the invention for a purpose including, but not limited to,one or more of the following: monitoring the location of the substrate,e.g., a balloon or other device; assessing physiological parameters,e.g., flow and perfusion; and targeting to a specific molecule. Inembodiments, “smart” agents that activate only in the presence of theirintended target are used with the device and methods of the invention.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and tacking at least a portion of the coating to anintervention site. In some embodiments, the tacking the coating portion(i.e. the portion of the coating) to the intervention site is uponstimulating the coating with a stimulation.

In some embodiments, the substrate comprises a balloon. In someembodiments, the portion of the balloon having coating thereon comprisesan outer surface of the balloon. In some embodiments, the outer surfaceis a surface of the balloon exposed to a coating prior to balloonfolding. In some embodiments, the outer surface is a surface of theballoon exposed to a coating following balloon folding. In someembodiments, the outer surface is a surface of the balloon exposed to acoating following balloon crimping. In some embodiments, the coatingcomprises a material that undergoes plastic deformation at pressuresprovided by inflation of the balloon. In some embodiments, the coatingcomprises a material that undergoes plastic deformation at a pressurethat is less than the rated burst pressure of the balloon.

In some embodiments, the coating comprises a material that undergoesplastic deformation at a pressure that is less than the nominalinflation pressure of the balloon. In some embodiments, the coatingcomprises a material that undergoes plastic deformation with at least 8ATM of pressure. In some embodiments, the coating comprises a materialthat undergoes plastic deformation with at least 6 ATM of pressure. Insome embodiments, the coating comprises a material that undergoesplastic deformation with at least 4 ATM of pressure. In someembodiments, the coating comprises a material that undergoes plasticdeformation with at least 2 ATM of pressure.

In some embodiments, the balloon is a compliant balloon. In someembodiments, the balloon is a semi-compliant balloon. In someembodiments, the balloon is a non-compliant balloon. In someembodiments, the balloon conforms to a shape of the intervention site.

In some embodiments, the balloon comprises a cylindrical portion. Insome embodiments, the balloon comprises a substantially sphericalportion. In some embodiments, the balloon comprises a complex shape. Insome embodiments, the complex shape comprises at least one of a doublenoded shape, a triple noded shape, a waisted shape, an hourglass shape,and a ribbed shape.

Some embodiments provide devices that can serve interventional purposesin addition to delivery of therapeutics, such as a cutting balloon. Insome embodiments, the substrate comprises a cutting balloon. In someembodiments, the cutting balloon comprises at least one tacking elementadapted to tack the coating to the intervention site. In someembodiments, the tacking element is adapted to secure the coating to thecutting balloon until inflation of the cutting balloon. In someembodiments, the tacking element comprises a wire. In some embodiments,the wire is shaped in the form of an outward pointing wedge. In someembodiments, the tacking element does not cut tissue at the interventionsite.

One illustration devices provided herein include a cutting balloon forthe treatment of vascular disease (e.g.; occluded lesions in thecoronary or peripheral vasculature). In this embodiment, the coating maybe preferentially located on the ‘cutting wire’ portion of the device.Upon deployment, the wire pushes into the plaque to provide the desiredtherapeutic ‘cutting’ action. During this cutting, the polymer and drugcoating is plastically deformed off of the wire by the combination ofcompressive and shear forces acting on the wire—leaving some or all ofthe coating embedded in the plaque and/or artery wall. A similarapproach may be applied to delivery of oncology drugs (a) directly totumors and/or, (b) to the arteries delivering blood to the tumors forsite-specific chemotherapy, and/or (c) to the voids left after theremoval of a tumor (lumpectomy). These oncology (as well as othernon-vascular) applications may not require the ‘cutting’ aspects andcould be provided by coatings directly onto the balloon or onto a sheathover the balloon or according to an embodiment wherein the coating formsa sheath over the deflated (pleated) balloon.

A cutting balloon embodiment described herein provides severaladvantages. Such embodiment allows for concentrating the mechanicalforce on the coating/wire as the balloon is inflated—the wire may serveto concentrate the point-of-contact-area of the balloon expansionpressure resulting in a much higher force for plastic deformation of thedrug and polymer coating vs, the non-cutting plain balloon which maydistribute the pressure over a much larger area (therefore lower forceproportional to the ratio of the areas). Embodiments involving a cuttingballoon provide for the use of polymers that would otherwise be toorigid (higher modulus) to deform from a non-cutting balloon.

Other embodiments provided herein are based on geometric configurationsof the device that optimize both the deformation and the bulk-migrationof the coating from the device. In one embodiment wherein the device isa cutting balloon, the (coated) wire of the cutting balloon is shapedlike a wedge, pointed outward.

Another embodiment provides catheter-based devices where thedrug-delivery formulation is delivered to the therapeutic site in thevasculature via inflation of a balloon.

One embodiment provides coated percutaneous devices (e.g.; balloons,whether cutting balloons or other balloon types) that, upon deploymentat a specific site in the patient, transfer some or all of thedrug-delivery formulation (5-10%, 10-25%, 25-50%, 50-90%, 90-99%,99-100%) to the site of therapeutic demand. In certain embodiments, theballoon is at least in part cylindrical as expanded or as formed. Incertain embodiments, the balloon is at least in part bulbous as expandedor as formed. In certain embodiments, the balloon is at least in partspherical as expanded or as formed. In certain embodiments, the balloonhas a complex shape as expanded or as formed (such as a double nodedshape, a triple noded shape, has a waist, and/or has an hourglass shape,for non-limiting example).

In some embodiments, transferring at least a portion of the active agentcomprises transferring at least about 3%, at least about 5%, at leastabout 10%>, at least about 20%, at least about 30%), greater than 35%,at least about 50%, at least about 75%, at least about 85%, at leastabout 90%, at least about 95%, and/or at least about 99% of the activeagent from the substrate. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,transferring transfers less than about 1%, less than about 5%, less thanabout 10%, less than about 15%, less than about 25%, at most about 35%,less than about 50%, less than about 70%, less than about 80%, and/orless than about 90% of the active agent absent stimulating at least oneof the coating and the substrate.

The term “adapted to transfer at least a portion” of the coating oractive agent to an intervention site refers to a device that is designedto transfer any portion of the coating or active agent to anintervention site.

The term “adapted to free” a portion of a coating and/or active agentfrom the substrate refers to a device, coating, and/or substrate that isdesigned to free a certain percentage of the coating and/or active agentfrom the substrate. As used herein, a device, coating, and/or substratethat is designed to free a certain percentage of the coating and/oractive agent from the substrate is designed to unrestrain the coatingand/or active agent from the substrate, and/or to remove any obstructionand/or connection the coating may have to the substrate (whether director indirect).

In some embodiments, the device is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limitingexample, the device is so adapted by substrate attributes (fornon-limiting example: substrate composition, substrate materials, shape,substrate deployment attributes, substrate delivery attributes,substrate pattern, and/or substrate texture), the delivery system of thesubstrate and coating (for non-limiting example: control over thesubstrate, control over the coating using the delivery system, the typeof delivery system provided, the materials of the delivery system,and/or combinations thereof), coating attributes (for non-limitingexample: selection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limitingexample, the substrate is so adapted by selection of the substratecomposition, substrate materials, shape, substrate deploymentattributes, substrate delivery attributes, substrate pattern, and/orsubstrate texture, and/or combinations thereof. For example, a ballooncan be designed to only partially inflate within the confines of theintervention site. Partial inflation can prevent a designated portion ofcoating from being freed.

In some embodiments, the coating is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limiting examplethe coating may be so adapted by selection of the active agent and/orthe polymer and/or the polymer-active agent composition, or by thecoating having a particular pattern—e.g. a ribbed pattern, a texturedsurface, a smooth surface, and/or another pattern, coating thickness,coating layers, and/or another physical and/or compositional attribute.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the substrate is so adapted by selection ofthe substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being freed.

In some embodiments, the coating is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example the coating may be so adapted by selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute.

In some embodiments, freeing at least a portion of the coating comprisesfreeing at least about 10%, at least about 20%, at least about 30%,greater than 35%, at least about 50%, at least about 75%) at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating from the substrate. In some embodiments, stimulatingdecreases the contact between the coating and the substrate. In someembodiments, freeing frees less than about 1%, less than about 5%, lessthan about 10%, less than about 15%, less than about 25%, at most about35%, less than about 50%), less than about 70%, less than about 80%,and/or less than about 90% of the coating absent stimulating at leastone of the coating and the substrate.

The term “adapted to dissociate” a portion of a coating and/or activeagent from the substrate refers to a device, coating, and/or substratethat is designed to dissociate a certain percentage of the coatingand/or active agent from the substrate. As used herein, a device,coating, and/or substrate that is designed to dissociate a certainpercentage of the coating and/or active agent from the substrate isdesigned to remove from association between the coating (and/or activeagent) and the substrate. Also and/or alternatively, as used herein, adevice, coating, and/or substrate that is designed to dissociate acertain percentage of the coating and/or active agent from the substrateis designed to separate the coating (and/or active agent) from thesubstrate. This separation may be reversible in some embodiments. Thisseparation may not be reversible in some embodiments.

In some embodiments, the device is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample, the device is so adapted by substrate attributes (fornon-limiting example: substrate composition, substrate materials, shape,substrate deployment attributes, substrate delivery attributes,substrate pattern, and/or substrate texture), the delivery system of thesubstrate and coating (for non-limiting example: control over thesubstrate, control over the coating using the delivery system, the typeof delivery system provided, the materials of the delivery system,and/or combinations thereof), coating attributes (for non-limitingexample: selection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample, the substrate is so adapted by selection of the substratecomposition, substrate materials, shape, substrate deploymentattributes, substrate delivery attributes, substrate pattern, and/orsubstrate texture, and/or combinations thereof. For example, a ballooncan be designed to only partially inflate within the confines of theintervention site. Partial inflation can prevent a designated portion ofcoating from being freed.

In some embodiments, the coating is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample the coating may be so adapted by selection of the active agentand/or the polymer and/or the polymer-active agent composition, or bythe coating having a particular pattern—e.g. a ribbed pattern, atextured surface, a smooth surface, and/or another pattern, coatingthickness, coating layers, and/or another physical and/or compositionalattribute.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the substrate is so adapted by selection ofthe substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being freed.

In some embodiments, the coating is adapted to dissociate a portion ofthe coating and/or active agent from the substrate to the interventionsite. For non-limiting example the coating may be so adapted byselection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute.

In some embodiments, dissociating at least a portion of the coatingcomprises dissociating at least about 10%, at least about 20%, at leastabout 30%, greater than 35%, at least about 50%), at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99%) of the coating from the substrate. In some embodiments,stimulating decreases the contact between the coating and the substrate.In some embodiments, dissociating dissociates less than about 1%), lessthan about 5%, less than about 10%, less than about 15%, less than about25%, at most about 35%), less than about 50%, less than about 70%, lessthan about 80%, and/or less than about 90% of the coating absentstimulating at least one of the coating and the substrate.

“Plastic deformation” as used herein is the change in the physical shapeof the coating by forces induced on the device. Plastic deformationresults in increasing the contact area of the coating on the tissue anddecreasing the contact area of the coating on the device. This change incontact area results in some or all of the coating being preferentiallyexposed to the tissue instead of the device. The terms “plasticdeformation” and “plastically deform,” as used herein in the context ofa coating, are intended to include the expansion of the coating materialbeyond the elastic limit of the material such that the material ispermanently deformed. “Elastic deformation” as used herein refers to areversible alteration of the form or dimensions of the object understress or strain, e.g., inflation pressure of a balloon substrate. Theterms “plastic deformation” and “plastically deform,” as used herein inthe context of a balloon or other substrate, are intended to include theexpansion of the substrate beyond the elastic limit of the substratematerial such that the substrate material is permanently deformed. Onceplastically deformed, a material becomes substantially inelastic andgenerally will not, on its own, return to its pre-expansion size andshape. “Residual plastic deformation” refers to a deformation capable ofremaining at least partially after removal of the inflation stress,e.g., when the balloon is deflated. “Elastic deformation” as used hereinrefers to a reversible alteration of the form or dimensions of theobject (whether it is the coating or the substrate) under stress orstrain, e.g., inflation pressure.

“Shear transfer” as used herein is the force (or component of forces)orthogonal to the device that would drive the coating away from thedevice substrate. This could be induced on the device by deployment,pressure-response from the surrounding tissue and/or in-growth of tissuearound the coating.

“Bulk migration” as used herein is the incorporation of the coatingonto/into the tissue provided by the removal of the device and/orprovided by degradation of the coating over time and/or provided byhydration of the coating over time. Degradation and hydration of thecoating may reduce the coating's cohesive and adhesive binding to thedevice, thereby facilitating transfer of the coating to the tissue.

One embodiment may described by analogy to contact printing whereby abiochemically active ‘ink’ (the polymer+drug coating) from a ‘die’ (thedevice) to the ‘stock’ (the site in the body).

The devices and methods described in conjunction with some of theembodiments provided herein are advantageously based on specificproperties provided for in the drug-delivery formulation. One suchproperty, especially well-suited for non-permanent implants such asballoon catheters, cutting balloons, etc. is ‘soft’ coating thatundergoes plastic deformation at pressures provided by the inflation ofthe balloon (range 2-25 ATM, typically 10-18 ATM). Another suchproperty, especially well-suited to permanent implants such as stents iscoatings where the polymer becomes ‘soft’ at some point after implanteither by hydration or by degradation or by combinations of hydrationand degradation.

Some embodiments provide devices that can advantageously be used inconjunction with methods that can aid/promote the transfer of thecoating. These include introducing stimuli to the coated device onceon-site in the body (where the device is delivered either transiently orpermanently). Such stimuli can be provided to induce a chemical response(light, heat, radiation, etc.) in the coating or can provide mechanicalforces to augment the transfer of the coating into the tissue(ultrasound, translation, rotation, vibration and combinations thereof).

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a mechanical stimulation. In someembodiments, the coating is freed from the substrate using a mechanicalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a mechanical stimulation. In some embodiments, thecoating is transferred from the substrate using a mechanicalstimulation. In some embodiments, the coating is transferred to theintervention site using a mechanical stimulation. In some embodiments,the coating is delivered to the intervention site using a mechanicalstimulation. In some embodiments, the mechanical stimulation is adaptedto augment the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the mechanical stimulation isadapted to initiate the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the mechanicalstimulation is adapted to cause the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, themechanical stimulation comprises at least one of a compressive force, ashear force, a tensile force, a force exerted on the coating from asubstrate side of the coating, a force exerted on the coating by thesubstrate, a force exerted on the coating from an external element, atranslation, a rotation, a vibration, and a combination thereof. In someembodiments, the external element is a part of the subject. In someembodiments, the external element is not part of the device. In someembodiments, the external element comprises a liquid. In someembodiments, the liquid is forced between the coating and the substrate.In some embodiments, the liquid comprises saline. In some embodiments,the liquid comprises water. In some embodiments, the mechanicalstimulation comprises a geometric configuration of the substrate thatmaximizes a shear force on the coating. In some embodiments, themechanical stimulation comprises a geometric configuration of thesubstrate that increases a shear force on the coating. In someembodiments, the mechanical stimulation comprises a geometricconfiguration of the substrate that enhances a shear force on thecoating.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a chemical stimulation. In someembodiments, the coating is freed from the substrate using a chemicalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a chemical stimulation. In some embodiments, the coatingis transferred from the substrate using a chemical stimulation. In someembodiments, the coating is transferred to the intervention site using achemical stimulation. In some embodiments, the coating is delivered tothe intervention site using a chemical stimulation. In some embodiments,the chemical stimulation comprises at least one of bulk degradation,interaction with a bodily fluid, interaction with a bodily tissue, achemical interaction with a non-bodily fluid, a chemical interactionwith a chemical, an acid-base reaction, an enzymatic reaction,hydrolysis, and combinations thereof. In some embodiments, the chemicalstimulation comprises bulk degradation of the coating. In someembodiments, the chemical stimulation comprises interaction of thecoating or a portion thereof with a bodily fluid. In some embodiments,the chemical stimulation comprises interaction of the coating or aportion thereof with a bodily tissue. In some embodiments, the chemicalstimulation comprises a chemical interaction of the coating or a portionthereof with a non-bodily fluid. In some embodiments, the chemicalstimulation comprises a chemical interaction of the coating or a portionthereof with a chemical. In some embodiments, the chemical stimulationcomprises an acid-base reaction. In some embodiments, the chemicalstimulation comprises an enzymatic reaction. In some embodiments, thechemical stimulation comprises hydrolysis.

In some embodiments, the chemical stimulation is adapted to augment thefreeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the chemical stimulation is adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the chemical stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the coating comprises amaterial that is adapted to transfer, free, and/or dissociate from thesubstrate when at the intervention site in response to an in-situenzymatic reaction resulting in a weak bond between the coating and thesubstrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a thermal stimulation. In someembodiments, the coating is freed from the substrate using a thermalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a thermal stimulation. In some embodiments, the coatingis transferred from the substrate using a thermal stimulation. In someembodiments, the coating is transferred to the intervention site using athermal stimulation. In some embodiments, the coating is delivered tothe intervention site using a thermal stimulation. In some embodiments,the thermal stimulation comprises at least one of a hot stimulus and acold stimulus adapted to augment the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation is adapted to cause the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation comprises at least one of a hot stimulus and a coldstimulus adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation comprises at least one of a hot stimulus and a coldstimulus adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a electromagnetic stimulation. In someembodiments, the coating is freed from the substrate using aelectromagnetic stimulation. In some embodiments, the coating isdissociated from the substrate using a electromagnetic stimulation. Insome embodiments, the coating is transferred from the substrate using aelectromagnetic stimulation. In some embodiments, the coating istransferred to the intervention site using a electromagneticstimulation. In some embodiments, the coating is delivered to theintervention site using a electromagnetic stimulation. In someembodiments, the electromagnetic stimulation comprises anelectromagnetic wave comprising at least one of a radio wave, a microwave, a infrared wave, near infrared wave, a visible light wave, anultraviolet wave, a X-ray wave, and a gamma wave. In some embodiments,the electromagnetic stimulation is adapted to augment the freeing,dissociation and/or transference of the coating from the substrate. Insome embodiments, the electromagnetic stimulation is adapted to initiatethe freeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the electromagnetic stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a some stimulation. In some embodiments,the coating is freed from the substrate using a some stimulation. Insome embodiments, the coating is dissociated from the substrate using asome stimulation. In some embodiments, the coating is transferred fromthe substrate using a some stimulation. In some embodiments, the coatingis transferred to the intervention site using a some stimulation. Insome embodiments, the coating is delivered to the intervention siteusing a some stimulation. In some embodiments, the some stimulationcomprises a sound wave, wherein the sound wave is at least one of anultrasound wave, an acoustic sound wave, and an infrasound wave. In someembodiments, the some stimulation is adapted to augment the freeing,dissociation and/or transference of the coating from the substrate. Insome embodiments, the some stimulation is adapted to initiate thefreeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the some stimulation is adapted to causethe freeing, dissociation and/or transference of the coating from thesubstrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a combination of at least two of amechanical stimulation, a chemical stimulation, an electromagneticstimulation, and a some stimulation.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate by extrusion.

Provided herein are device geometries that maximize the shear forces onthe coating. Such geometric design of the device provides twoadvantages: (1) increases (concentrates) the force to plastically deformthe drug and polymer coating (2) decreases the force of adhesion of thecoating. For example, a wedge-shape aligns the forces of deformationalong a shear plan as opposed to direct compression. This embodimentprovides for: (1) increased efficiency in terms of % of the coatingtransferred (2) increased precision in amount transferred on acase-by-case basis (3) utilization of ‘harder/stiffer’ materials(biopolymers) that would otherwise not deform and/or not bulk-migrateunder deployment conditions (4) minimize the chance of particulateshedding via purposefully designing the shape and direction of both thedeformation and bulk migration. For example for a wedge, particles wouldbe less likely because the coating would be pre-disposed as a shear fromthe device in a sheet form—with the use of soft materials, this may beillustrated as a coating of silicone caulk being extruded from thepressure of a rod being pushed into a mattress.

Another embodiment provide a geometric arrangement of the coatingwhereby layers. e.g. a laminate structure, are provided in the coatingto modulate and control the plastic deformation, shearing andbulk-migration of the coating into the tissue.

One embodiment provides coated substrates that, upon deployment at aspecific site in the patient, transfer some or all of the coating(5-10%, 10-25%, 25-50%, 50-90%, 90-99%, 99-100%) to the site oftherapeutic demand.

In some embodiments, the device further comprises a release agent. Insome embodiments, the release agent is biocompatible. In someembodiments, the release agent is non-biocompatible. In someembodiments, the release agent comprises a powder. In some embodiments,the release agent comprises a lubricant. In some embodiments, therelease agent comprises a surface modification of the substrate.

In some embodiments, the release agent comprises a physicalcharacteristic of the coating. In some embodiments, the physicalcharacteristic of the coating comprises a pattern. In some embodiments,the pattern is a textured surface on the substrate side of the coating,wherein the substrate side of the coating is the part of the coating onthe substrate. In some embodiments, the pattern is a textured surface onthe intervention site side of the coating, wherein the intervention siteside of the coating is the part of the coating that is transferred to,and/or delivered to, and/or deposited at the intervention site.

In some embodiments, the release agent comprises a viscous fluid. Insome embodiments, the viscous fluid comprises oil. In some embodiments,the viscous fluid is a fluid that is viscous relative to water. In someembodiments, the viscous fluid is a fluid that is viscous relative toblood. In some embodiments, the viscous fluid is a fluid that is viscousrelative to urine. In some embodiments, the viscous fluid is a fluidthat is viscous relative to bile. In some embodiments, the viscous fluidis a fluid that is viscous relative to synovial fluid. In someembodiments, the viscous fluid is a fluid that is viscous relative tosaline. In some embodiments, the viscous fluid is a fluid that isviscous relative to a bodily fluid at the intervention site.

In some embodiments, the release agent comprises a gel.

In some embodiments, the release agent comprises at least one of theactive agent and another active agent. The active agent may be placed onthe substrate prior to the coating in order to act as the release agent.The active agent may be a different active agent than the active agentin the coating. The active agent that is the release agent may providefor a second source of drug to be delivered to the intervention site oranother location once the coating is released from (or transferred from,or freed from, or dissociated from) the substrate.

In some embodiments, the release agent comprises a physicalcharacteristic of the substrate. In some embodiments, the physicalcharacteristic of the substrate comprises at least one of a patternedcoating surface and a ribbed coating surface. In some embodiments, thepatterned coating surface comprises a stent framework. In someembodiments, the ribbed coating surface comprises an undulatingsubstrate surface. In some embodiments, the ribbed coating surfacecomprises an substrate surface having bumps thereon.

In some embodiments, the release agent comprises a property that iscapable of changing at the intervention site. In some embodiments, theproperty comprises a physical property. In some embodiments, theproperty comprises a chemical property. In some embodiments, the releaseagent is capable of changing a property when in contact with at leastone of a biologic tissue and a biologic fluid. In some embodiments, therelease agent is capable of changing a property when in contact with anaqueous liquid.

In some embodiments, the release agent is between the substrate and thecoating.

Methods of Manufacturing Generally

In some embodiments, a coating is formed on the substrate by a processcomprising depositing a polymer and/or the active agent by an e-RESS, ane-SEDS, or an e-DPC process. In some embodiments, the process of formingthe coating provides improved adherence of the coating to the substrateprior to deployment of the device at the intervention site andfacilitates dissociation of the coating from the substrate at theintervention site. In some embodiments, the coating is formed on thesubstrate by a process comprising depositing the active agent by ane-RESS, an e-SEDS, or an e-DPC process without electrically charging thesubstrate. In some embodiments, the coating is formed on the substrateby a process comprising depositing the active agent on the substrate byan e-RESS, an e-SEDS, or an e-DPC process without creating an electricalpotential between the substrate and a coating apparatus used to depositthe active agent.

Means for creating the bioabsorbable polymer(s)+drug (s) coating of thedevice with or without a substrate:

-   -   Spray coat the coating-form with drug and polymer as is done in        Micell process (e-RESS, e-DPC, compressed-gas sintering).    -   Perform multiple and sequential coating-sintering steps where        different materials may be deposited in each step, thus creating        a laminated structure with a multitude of thin layers of        drug(s), polymer(s) or drug+polymer that build the final device.    -   Perform the deposition of polymer(s)+drug(s) laminates with the        inclusion of a mask on the inner (luminal) surface of the        device. Such a mask could be as simple as a non-conductive        mandrel inserted through the internal diameter of the coating        form. This masking could take place prior to any layers being        added, or be purposefully inserted after several layers are        deposited continuously around the entire coating-form.

In some embodiments, the coating comprises a microstructure. In someembodiments, particles of the active agent are sequestered orencapsulated within the microstructure. In some embodiments, themicrostructure comprises microchannels, micropores and/or microcavities.In some embodiments, the microstructure is selected to allow sustainedrelease of the active agent. In some embodiments, the microstructure isselected to allow controlled release of the active agent.

Other methods for preparing the coating include solvent based coatingmethods and plasma based coating methods. In some embodiments, thecoating is prepared by a solvent based coating method. In someembodiments, the coating is prepared by a solvent plasma based coatingmethod.

Another advantage of the present invention is the ability to create adelivery device with a controlled (dialed-in) drug-elution profile. Viathe ability to have different materials in each layer of the laminatestructure and the ability to control the location of drug(s)independently in these layers, the method enables a device that couldrelease drugs at very specific elution profiles, programmed sequentialand/or parallel elution profiles. Also, the present invention allowscontrolled elution of one drug without affecting the elution of a seconddrug (or different doses of the same drug).

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted totransfer from the substrate to an intervention site upon stimulating thecoating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without electricallycharging the substrate, wherein forming the coating results in at leasta portion of the coating being adapted to transfer from the substrate toan intervention site upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without creating anelectrical potential between the substrate and a coating apparatus usedin the at least one e-RESS, an e-SEDS, and an e-DPC process, whereinforming the coating results in at least a portion of the coating beingadapted to transfer from the substrate to an intervention site uponstimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to transferfrom the substrate to an intervention site upon stimulating the coatingwith a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted tofree from the substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to free fromthe substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted todissociate from the substrate upon stimulating the coating with astimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to dissociatefrom the substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted todeliver to the intervention site upon stimulating the coating with astimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to deliver tothe intervention site upon stimulating the coating with a stimulation.

In some embodiments, the e-RESS, the e-SEDS, and/or the e-DPC processused in forming the coating is performed without electrically chargingthe substrate. In some embodiments, the e-RESS, the e-SEDS, and/or thee-DPC process used in forming the coating is performed without creatingan electrical potential between the substrate and the coating apparatusused in the e-RESS, the e-SEDS, and/or the e-DPC process.

In some embodiments, forming the coating results in the coating adheringto the substrate prior to the substrate reaching the intervention site.

Some embodiments further comprise providing a release agent on thesubstrate. In some embodiments, providing the release agent step isperformed prior to the forming the coating step. In some embodiments,the release agent comprises at least one of: a biocompatible releaseagent, a non-biocompatible release agent, a powder, a lubricant, asurface modification of the substrate, a viscous fluid, a gel, theactive agent, a second active agent, a physical characteristic of thesubstrate. In some embodiments, the physical characteristic of thesubstrate comprises at least one of: a patterned coating surface of thesubstrate, and a ribbed surface of the substrate. In some embodiments,the release agent comprises a property that is capable of changing atthe intervention site. In some embodiments, the property comprises aphysical property. In some embodiments, the property comprises achemical property. In some embodiments, the release agent is capable ofchanging a property when in contact with at least one of a biologictissue and a biologic fluid. In some embodiments, the release agent iscapable of changing a property when in contact with an aqueous liquid.In some embodiments, the coating results in a coating property thatfacilitates transfer of the coating to the intervention site. In someembodiments, the coating property comprises a physical characteristic ofthe coating. In some embodiments, the physical characteristic comprisesa pattern.

In some embodiments, forming the coating facilitates transfer of thecoating to the intervention site.

In some embodiments, transferring, freeing, dissociating, depositing,and/or tacking step comprises softening the polymer by hydration,degradation or by a combination of hydration and degradation. In someembodiments, the transferring, freeing, dissociating, depositing, and/ortacking step comprises softening the polymer by hydrolysis of thepolymer.

In some embodiments, the providing step comprises forming the coating bya solvent based coating method. In some embodiments, the providing stepcomprises forming the coating by a solvent plasma based method.

In some embodiments, providing the device comprises depositing aplurality of layers on the substrate to form the coating, wherein atleast one of the layers comprises the active agent. In some embodiments,at least one of the layers comprises a polymer. In some embodiments, thepolymer is bioabsorbable. In some embodiments, the active agent and thepolymer are in the same layer, in separate layers, or form overlappinglayers. In some embodiments, the plurality of layers comprise fivelayers deposited as follows: a first polymer layer, a first active agentlayer, a second polymer layer, a second active agent layer and a thirdpolymer layer.

EXAMPLES

The following examples are provided to illustrate selected embodiments.They should not be considered as limiting the scope of the invention,but merely as being illustrative and representative thereof. For eachexample listed herein, multiple analytical techniques may be provided.Any single technique of the multiple techniques listed may be sufficientto indicate the parameter and/or characteristic being tested, or anycombination of techniques may be used to indicate such parameter and/orcharacteristic. Those skilled in the art will be familiar with a widerange of analytical techniques for the characterization of drug/polymercoatings. Techniques presented here, but not limited to, may be used toadditionally and/or alternatively characterize specific properties ofthe coatings with variations and adjustments employed which would beobvious to those skilled in the art.

Sample Preparation

Generally speaking, coatings on stents, on balloons, on coupons, onother substrates, or on samples prepared for in-vivo models are preparedas herein. Nevertheless, modifications for a given analytical method arepresented within the examples described, and/or would be obvious to onehaving skill in the art. Thus, numerous variations, changes, andsubstitutions will now occur to those skilled in the art withoutdeparting from the invention. It should be understood that variousalternatives to the embodiments of the invention described herein andexamples provided may be employed in practicing the invention andindicating the parameters and/or characteristics described.

Coatings on Balloons

Coated balloons as described herein and/or made by a method disclosedherein are prepared. In some examples, the coated balloons have atargeted coating thickness of ˜15 microns (˜5 microns of active agent).In some examples, the coating process is PDPDP (Polymer, sinter, Drug,Polymer, sinter, Drug, Polymer, sinter) using deposition of drug in drypowder form and deposition of polymer particles by RESS methods andequipment described herein. In the illustrations herein, resultingcoated balloons may have a 3-layer coating comprising polymer (forexample, PLGA) in the first layer, drug (for example, rapamycin) in asecond layer and polymer in the third layer, where a portion of thethird layer is substantially drug free (e.g. a sub-layer within thethird layer having a thickness equal to a fraction of the thickness ofthe third layer). As described layer, the middle layer (or drug layer)may be overlapping with one or both first (polymer) and third (polymer)layer. The overlap between the drug layer and the polymer layers isdefined by extension of polymer material into physical space largelyoccupied by the drug. The overlap between the drug and polymer layersmay relate to partial packing of the drug particles during the formationof the drug layer. When crystal drug particles are deposited on top ofthe first polymer layer, voids and or gaps may remain between drycrystal particles. The voids and gaps are available to be occupied byparticles deposited during the formation of the third (polymer) layer.Some of the particles from the third (polymer) layer may rest in thevicinity of drug particles in the second (drug) layer. When thesintering step is completed for the third (polymer) layer, the thirdpolymer layer particles fuse to form a continuous film that forms thethird (polymer) layer. In some embodiments, the third (polymer) layerhowever will have a portion along the longitudinal axis of the stentwhereby the portion is free of contacts between polymer material anddrug particles. The portion of the third layer that is substantially ofcontact with drug particles can be as thin as 1 nanometer.

Polymer-coated balloons having coatings comprising polymer but no drugare made by a method disclosed herein and are prepared having a targetedcoating thickness of, for example, about 0.5, 1, 2, 3, 4, 5, 10, 15, 20,25, 30, 35, 40, 45, or 50 microns, depending in part on whether thecoating expands upon hydration and if so whether it is hydrated. Inembodiments, the coating thickness is 1-5 microns. In other embodiments,it is 1-10 microns.

An example coating process is PPP (PLGA, sinter, PLGA, sinter, PLGA,sinter) using RESS methods and equipment described herein. Thesepolymer-coated balloons may be used as control samples in some of theexamples, infra.

In some examples, the balloons are made of a compliant polymer. In someexamples, the balloons are made of a non-compliant polymer. The balloonsmay be, in some examples, 5 to 50 mm in length, preferably 10-20 mm inlength.

Balloons can be coated while inflated, and later compacted, or they canbe coated while uninflated. If a balloon is coated while inflated andlater folded or otherwise compacted, then a portion of the coating canbe protected during insertion by virtue of being disposed within theportion of the balloon that is not exposed until inflation. The coatingcan also be protected by using a sheath or other covering, as describedin the art for facilitating insertion of an angioplasty balloon.

The coating released from a balloon may be analyzed (for example, foranalysis of a coating band and/or coating a portion of the balloon).Alternatively, in some examples, the coating is analyzed directly on theballoon. This coating, and/or coating and balloon, may be sliced intosections which may be turned 90 degrees and visualized using the surfacecomposition techniques presented herein or other techniques known in theart for surface composition analysis (or other characteristics, such ascrystallinity, for example). In this way, what could be an analysis ofcoating composition through a depth when the coating is on the balloonor as removed from the balloon (i.e. a depth from the ab luminal surfaceof the coating to the surface of the removed coating that once contactedthe balloon or a portion thereof), becomes a surface analysis of thecoating which can, for example, indicate the layers in the slice ofcoating, at much higher resolution. Residual coating on an extractedballoon also can be analyzed and compared to the amount of coating on anunused balloon, using, e.g., HPLC, as noted herein. Coating removed fromthe balloon, or analyzed without removal and/or release from theballoon, may be treated the same way, and assayed, visualized, and/orcharacterized as presented herein using the techniques described and/orother techniques known to a person of skill in the art.

Sample Preparation for In-Vivo Models

Devices comprising balloons having coatings disclosed herein aredeployed in the porcine coronary arteries of pigs (domestic swine,juvenile farm pigs, or Yucatan miniature swine). Porcine coronaryangioplasty is exploited herein since such model yields results that arecomparable to other investigations assaying neointimal hyperplasia inhuman subjects. The balloons are expanded to a 1:1.1 balloon:arteryratio. At multiple time points, animals are euthanized (e.g., t=1 day, 7days, 14 days, 21 days, and 28 days), the tissue surrounding theintervention site is extracted, and assayed.

Devices comprising balloons having coatings disclosed hereinalternatively are implanted in the common iliac arteries of New Zealandwhite rabbits. The balloons are expanded to a 1:1.1 balloon:arteryratio. At multiple time points, animals are euthanized (e.g., t=1 day, 7days, 14 days, 21 days, and 28 days), the tissue surrounding theintervention site is extracted, and assayed.

Example 1: Cutting Balloons

Cutting Balloon (1)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a polymer and an active agent.The coated cutting balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. Upon deflation and removal of the cutting balloon from theintervention site, at least about 5% to at least about 30% of thecoating is freed from the surface of the cutting balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The intervention site is a vascular lumen wall. Uponinflation of the cutting balloon, at least about 50%> of the coating isfreed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus −20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 1 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon, about 5% to about 15% ofthe coating is freed from the device resulting in delivery of −2.0 μg ofdrug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 1 is employed. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate −1-2months) and sirolimus with total loading of sirolimus −20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment. A serum sample as well as a tissuesample from the deployment site is collected.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is anangioplasty catheter and the substrate is the balloon of the catheter)may be used to determine the percent of coating freed, dissociated,and/or transferred from the device. In some instances, an assessment ofthe device following the procedure alone is sufficient to assess theamount freed or dissociated from the substrate, without determination ofthe amount delivered to the intervention site. Additionally, where adetermination of improvement and/or disease treatment is desired, levelsof proinflammatory markers could be tested to indicate improvementand/or treatment of a disease and/or ailment, for example, by testinghigh sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6),interleukin-{circumflex over (ι)}β (IL-I β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe indicated by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, ID.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (2)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated using a solution-based system (spray or dipcoating) comprising a polymer and an active agent. The coated cuttingballoon is positioned at the intervention site. The balloon is inflatedto at least 25% below its nominal inflation pressure. At least about 5%to at least about 30% of the coating is freed from the surface of thecutting balloon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process using a sprayand/or dip coating process is employed. The intervention site is avascular lumen wall. Upon inflation of the cutting balloon, at leastabout 50% of the coating is freed from the device at the interventionsite.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus −20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and coatingprocess using a spray and/or dip coating process is employed. Theintervention site is a coronary artery. Upon inflation of the cuttingballoon, about 5% to about 15% of the coating is freed from the deviceresulting in delivery of −2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processusing a spray and/or dip coating process is employed. The interventionsite is a cavity resulting from removal of a tumor. Upon inflation ofthe cutting balloon, at least about 75% of the coating is transferredfrom the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate −1-2months) and sirolimus with total loading of sirolimus −20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and scrum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is anangioplasty catheter and the substrate is the balloon of the catheter)may be used to determine the percent of coating freed, dissociated,and/or transferred from the device. In some instances, an assessment ofthe device following the procedure alone is sufficient to assess theamount freed or dissociated from the substrate, without determination ofthe amount delivered to the intervention site. Additionally, where adetermination of improvement and/or disease treatment is desired, levelsof proinflammatory markers could be tested to indicate improvementand/or treatment of a disease and/or ailment, for example, by testinghigh sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6),interleukin-{tilde over (ι)}β (IL-I β), and/or monocyte chemoattractantprotein-1 (MCP-1). The release kinetics of the drug may be indicated byplotting the sirolimus concentrations at the timepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inusing spray and/or dip coating process is secured to a balloon catheter.A segment of optically clear TYGON® B-44-3 tubing with O.D.=0.125″,ID.=0.0625″ (Available from McMaster-Carr Part Number: 5114K11(www.mcmaster.com)) is filled with phosphate-buffered saline solutionand immersed in a water bath at 37° C. to mimic physiological conditionsof deployment into a subject. The coated balloon is inserted into thetubing and the balloon is inflated to at least 25% below the balloon'snominal pressure to mechanically transfer the coating from the balloonto the tubing wall. The balloon is deflated and removed from the tubing.Optical microscopy is performed on the tubing and/or the balloon (whichis inflated to at least 25% below the balloon's nominal pressure, atleast) to determine the presence and amount of coating transferred tothe tubing and/or the amount of coating freed, dissociated, and/ortransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (3)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a release agent, a polymer and anactive agent. The coated cutting balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. At least about 5% to at least about 50% ofthe coating is freed from the surface of the cutting balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example2 is employed. The intervention site is a vascular lumen wall. Uponinflation of the cutting balloon, at least about 50%> of the coating isfreed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus −20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 2 is employed. The intervention site is a coronaryartery. The release agent is ePTFE powder. Upon inflation of the cuttingballoon, about 5% to about 15% of the coating is freed from the deviceresulting in delivery of −2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜9 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 2 is employed. The release agent a micronized activeagent or another active agent in a micronized form. The interventionsite is a cavity resulting from removal of a tumor. Upon inflation ofthe cutting balloon, at least about 75%> of the coating is transferredfrom the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate −1-2months) and sirolimus with total loading of sirolimus −20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment. The tissue and serum samples may besubjected to analysis for sirolimus concentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is an angioplasty catheter and the substrate is theballoon of the catheter) may be used to determine the percent of coatingfreed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto indicate improvement and/or treatment of a disease and/or ailment,for example, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-{tilde over (ι)}β (IL-I β), and/ormonocyte chemoattractant protein-1 (MCP-1). The release kinetics of thedrug may be indicated by plotting the sirolimus concentrations at thetimepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 2 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, ID.=0.0625″ (Available fromMcMaster-Carr Part Number 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingtransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (4)—Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a polymer and an active agent.The coated cutting balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. At least about 10%> to at least about 50%> of the coating isfreed from the surface of the cutting balloon and is deposited at theintervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜9 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example3 is employed. The intervention site is a vascular lumen wall. Uponinflation of the cutting balloon, at least about 50%> of the coating isfreed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus −20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 3 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon, about 5% to about 15% ofthe coating is freed from the device resulting in delivery of −2.0 μg ofdrug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 3 is employed. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75%> of the coating is transferred from thedevice to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate −1-2months) and sirolimus with total loading of sirolimus −20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is acutting angioplasty catheter and the substrate is the cutting balloon ofthe catheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto indicate improvement and/or treatment of a disease and/or ailment,for example, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-{tilde over (ι)}β (IL-I β), and/ormonocyte chemoattractant protein-1 (MCP-1). The release kinetics of thedrug may be indicated by plotting the sirolimus concentrations at thetimepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 3 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, ID.=0.0625″ (Available fromMcMaster-Carr Part Number 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (5)—Mechanical and Chemical Stimulation to Free theCoating

A cutting balloon is coated with a formulation comprising a base layerof methyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+paclitaxel with total dose of paclitaxel approx. 0.5 μg/mm2 of thewire. The coating and sintering process is similar to that as describedin Example 1. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The coated cuttingballoon is positioned at the intervention site. The balloon ispressurized to at least to at least 25% below its nominal inflationpressure. Upon pressurization of the cutting balloon in the diseasedartery, at least about 10% to at least about 30% of the coating isreleased into the intervention site and upon depressurization andremoval of the device, this material is deposited at the interventionsite.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon.

In one example, a base layer of methyl acrylate-methacrylic acidcopolymer is formed and additional layers of the coating is about 50:50PLGA-Ester End Group, MW˜19 kD, degradation rate −1-2 months or about50:50 PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days.The active agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The intervention site isa vascular lumen wall. Upon inflation of the cutting balloon, at leastabout 50% of the coating is freed from the device at the interventionsite.

In another example, a cutting balloon is coated with a base layer ofmethyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+sirolimus with total loading of sirolimus −20μ. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. The balloon is constructed of a semipermable polymer.The pressurization medium is pH 8 phosphate buffer. Upon inflation ofthe cutting balloon, about 5% to about 15% of the coating is freed fromthe device resulting in delivery of −2.0 μg of drug delivered to theartery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 1 is employed. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a cutting balloon coated with a formulationof about 50:50 PLGA-Ester End Group (MW˜19 kD, degradation rate −1-2months) and sirolimus with total loading of sirolimus −20 μg with thecoating preferentially on the wire of the cutting balloon. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is ancutting angioplasty catheter and the substrate is the cutting balloon ofthe catheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto indicate improvement and/or treatment of a disease and/or ailment,for example, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-{tilde over (ι)}β (IL-I β), and/ormonocyte chemoattractant protein-1 (MCP-1). The release kinetics of thedrug may be indicated by plotting the sirolimus concentrations at thetimepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-vitro testing: One sample of the coated cutting balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, ID.=0.0625″ (Available fromMcMaster-Carr Part Number 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Example 2: Drug-Delivery Balloon Catheters

Drug-Delivery BALLOON (1)—Compliant Balloon

A compliant balloon is coated with a material comprising a polymer andan active agent. The coated compliant balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of the compliantballoon from the intervention site, at least about 5% to at least about30%> of the coating is freed from the surface of the compliant balloonand is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, M-˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The intervention site is a vascular lumen wall. Uponinflation of the compliant balloon, at least about 50% of the coating isfreed from the device at the intervention site.

In another example, a compliant balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus −20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. Upon inflation of the compliant balloon, about 5% toabout 15% of the coating is freed from the device resulting in deliveryof −2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate −1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate −28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the compliant balloon, at least about 75%of the coating is transferred from the device to the intervention site.

In-vivo testing: A group of 27 New Zealand white rabbits is prepared fora Seldinger procedure using a compliant balloon coated with aformulation of about 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate −1-2 months) and sirolimus with total loading of sirolimus −20 μg.The device is placed at a coronary artery intervention site with theassistance of fluoroscopy to aid in positioning the device at the samelocation in each subject. Six animals are subjected to the procedureusing a coated balloon that does not have sirolimus in the coating.After deployment and removal of the device, 3 control animals aresacrificed at 1 hour post deployment and serum and tissue samples arecollected. The 3 remaining control animals are sacrificed at 56 dayspost deployment. During the course of the study, serum samples arecollected from control and drug-treated animals every five days. Thedrug treated animals, 3 each, are sacrificed at 1 hour, 24 hours, 7days, 14 days, 28 days, 42 days and 56 days post deployment. The tissueand serum samples may be subjected to analysis for sirolimusconcentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is a cutting angioplasty catheter and the substrateis the balloon of the catheter) may be used to determine the percent ofcoating freed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto indicate improvement and/or treatment of a disease and/or ailment,for example, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-{tilde over (ι)}β (IL-I β), and/ormonocyte chemoattractant protein-1 (MCP-1). The release kinetics of thedrug may be indicated by plotting the sirolimus concentrations at thetimepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to indicate the treatmentresults for each subject.

In-vitro testing: One sample of the coated compliant balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, ID.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon.

Method for the determination of sirolimus levels: Media may be assayedfor sirolimus content using HPLC. Calibration standards containing knownamounts of drug are to determine the amount of drug eluted, or thecontent of a particular sample. The multiple peaks present for thesirolimus (also present in the calibration standards) are added to givethe amount of drug eluted at that time period (in absolute amount and asa cumulative amount eluted) or as an amount of drug in a particularsample. HPLC analysis is performed using Waters HPLC system, set up andrun on each sample as provided in the Table 1 below using an injectionvolume of 100 microL.

TABLE 1 Time point % Ammonium Acetate Flow Rate (minutes) % Acetonitrile(0.5%), pH 7.4 (mL/min) 0.00 10 90 1.2 1.00 10 90 1.2 12.5 95 5 1.2 13.5100 0 1.2 14.0 100 0 3 16.0 100 0 3 17.0 10 90 2 20.0 10 90 0

In-vitro Mass Loss test: One sample of the coated compliant balloonprepared in Example 1 is weighed on a microbalance and then secured to aballoon catheter. A segment of optically clear TYGON® B-44-3 tubing withO.D.=0.125″, ID.=0.0625″ (Available from McMaster-Carr Part Number:5114K11 (www.mcmaster.com) is filled with phosphate-buffered salinesolution and immersed in a water bath at 37° C. to mimic physiologicalconditions of deployment into a subject. The coated balloon is insertedinto the tubing and the balloon is inflated to at least 25% below theballoon's nominal pressure to mechanically transfer the coating from theballoon to the tubing wall. The balloon is deflated and removed from thetubing. After drying, the balloon is removed from the guidewire, furtherdried and weighed on a microbalance. Comparison of the pre- andpost-deployment weights indicates how much coating is freed,dissociated, and/or transferred from the balloon. This analysis mayinstead and/or alternatively include testing of the tubing to determinethe amount of coating freed, dissociated, and/or transferred from thedevice during this in-vitro test.

In-vitro Coating test: One sample of the coated compliant balloonprepared in Example 1 is secured to a balloon catheter. A segment ofoptically clear TYGON® B-44-3 tubing with O.D.=0.125″, ID.=0.0625″(Available from McMaster-Carr Part Number: 5114K11 (www.mcmaster.com))is filled with phosphate-buffered saline solution and immersed in awater bath at 37° C. to mimic physiological conditions of deploymentinto a subject. The coated balloon is inserted into the tubing and theballoon is inflated to at least 25% below the balloon's nominal pressureto mechanically transfer the coating from the balloon to the tubingwall. The balloon is deflated and removed from the tubing. The sectionof tubing exposed to the deployed balloon is cut away from the remainderof the tubing and the interior of the excised tubing rinsed with a smallamount of ethanol and an amount of methylene chloride to make up 25 mLtotal volume of rinsings which are collected in a flask for analysis.Analysis by HPLC as described above is performed to determine the amountof material freed, dissociated, and/or transferred from the balloon.This analysis may instead and/or alternatively include testing of thesubstrate itself to determine the amount of coating freed, dissociated,and/or transferred from the device during this in-vitro test.

In-vitro testing:: One sample of the coated compliant balloon preparedin Example 1 is secured to a balloon catheter. A segment of resectedcoronary artery from Yucatan miniature swine is positionally fixed andfilled with phosphate-buffered saline solution and immersed in a waterbath at 37° C. to mimic physiological conditions of deployment into asubject. The coated balloon is inserted into the artery and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the arterial wall.The balloon is deflated and removed from the artery. The section ofartery exposed to the deployed balloon is cut away from the remainder ofthe artery section, placed into a tissue homnogonizer and thehomogonized material is extracted with methylene chloride to make up 25mL total volume of rinsings which are collected in a flask for analysis.Analysis by HPLC as described above is performed to determine the amountof material freed, dissociated, and/or transferred from the balloon.This analysis may instead and/or alternatively include testing of thesubstrate itself to determine the amount of coating freed, dissociated,and/or transferred from the device during this in-vitro test.

For embodiments related to non-vascular or non-lumenal applications,e.g. a tumor site or other cavity or a cannulized site, the sametechnique is employed with the modification that the tissue to beassayed is resected from the tissue adjoining cavity receiving drugtreatment.

In-vitro testing:: One sample of the coated compliant balloon preparedin Example 1 is secured to a balloon catheter. A segment of resectedcoronary artery from Yucatan miniature swine is positionally fixed andfilled with phosphate-buffered saline solution and immersed in a waterbath at 37° C. to mimic physiological conditions of deployment into asubject. The coated balloon is inserted into the artery and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the arterial wall.The balloon is deflated and removed from the artery. The section ofartery exposed to the deployed balloon is cut away from the remainder ofthe artery section and incised lengthwise to lay open the artery.Optical microscopy is performed on the interior of artery to determinethe presence and amount of coating transferred to the artery and/or theamount of coating transferred from the balloon. The tissue sample isalso subjected to TEM-SEM analysis.

In-vitro testing of release kinetics: One sample of the coated compliantballoon with total loading of sirolimus −20 μg prepared in Example 1 issecured to a balloon catheter. A flask containing exactly 25 mL of pH7.4 aqueous phosphate buffer equilibrated to 37° C. equipped formagnetic stirring is prepared. Into this flask is placed the coatedballoon and the catheter portion of the apparatus is secured such thatthe balloon does not touch the sides of the flask. The balloon isinflated to 120 psi with sterile water. Aliquots of 100 μL are removedprior to addition of the balloon, after placement of the balloon butprior to inflation of the balloon, and at regular time intervals of 2,4, 6, 8, 10, 12, and 14 minutes. Upon removal of each aliquot anequivalent volume of aqueous buffer is added to maintain the volume at25 mL. The aliquots are analyzed by HPLC as described above for theconcentration of sirolimus.

In-vitro testing for distal flow particulates: One sample of the coatedcompliant balloon prepared in Example 1 is secured to a guidewireincorporating a porous filter of 100 micron pore size, such as theCordis AngioGuard emboli capture guidewire. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, ID.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing, the proximal end of thetubing surrounding the guidewire sealed with epoxy, and a hypodermicneedle which is attached to an infusion pump and reservoir of 37° C.phosphate-buffered saline solution is inserted into the tubing proximalto the balloon assembly. The flow of saline is commenced, the distalfilter is deployed and the balloon is inflated to at least 25% below theballoon's nominal pressure to mechanically transfer the coating from theballoon to the tubing wall. The balloon is deflated and removed from thetubing. The filter is deployed for 5 minutes after removal of theballoon, the flow of saline is halted, the tubing cut adjacent to theepoxy seal, the filter retracted and removed from the tubing. Thecontent of the filter is analyzed.

In-vitro testing for distal flow particulates: One sample of the coatedcompliant balloon prepared in Example 1 is secured to a guidewire. Asegment of optically clear TYGON® B-44-3 tubing with O.D.=0.125″,ID.=0.0625″ (Available from McMaster-Carr Part Number: 5114K11(www.mcmaster.com)) is filled with phosphate-buffered saline solutionand immersed in a water bath at 37° C. to mimic physiological conditionsof deployment into a subject and the distal end of the tubing isconnected to a turbidity light scattering detector as described inAnalytical Ultracentrifugation of Polymers and Nanoparticles, W. Machtleand L. Borger, (Springer) 2006, p. 41. The coated balloon is insertedinto the proximal end of the tubing, the proximal end of the tubingsurrounding the guidewire sealed with epoxy, and a hypodermic needlewhich is attached to an infusion pump and reservoir of 37° C.phosphate-buffered saline solution is inserted into the tubing proximalto the balloon assembly. The flow of saline is commenced, a baseline forlight transmission through the detector is established and the balloonis inflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the tubing wall.The balloon is deflated and removed from the tubing. The flow ismaintained for 10 minutes after removal of the balloon, and the flow isanalyzed for the presence of particles based on detector response.

Drug-Delivery Balloon (2)—Non-Compliant Balloon

A non-compliant balloon is coated with a material comprising a polymerand an active agent. The coated non-compliant balloon is positioned atthe intervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of thenon-compliant balloon from the intervention site, at least about 5% toat least about 30% of the coating is freed from the surface of thenon-compliant balloon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is about 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The intervention site is a vascular lumen wall. Uponinflation of the non-compliant balloon, at least about 50%) of thecoating is freed from the device at the intervention site.

In another example, a non-compliant balloon is coated with a formulationof PLGA+sirolimus with total loading of sirolimus −20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. Upon inflation of the non-compliant balloon, about 5%>to about 15%> of the coating is freed from the device resulting indelivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is about 50:50 PLGA-EsterEnd Group, MW˜19 kD, degradation rate −1-2 months or about 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate −28 days. Theactive agent is a chemotherapeutic agent. Equipment and coating processsimilar to Example 1 is employed. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the non-compliantballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo and/or in-vitro testing may be performed according to themethods described herein.

Example 3: In Vivo Delivery of Rapamycin from Coated Balloons SirolimusCoated Balloon Formulation Tested in Rabbits

GHOST Rapid Exchange (Rx) Catheter was used in this example, Ghost3.0×18 mm Rx catheter balloons were coated and used in animal study. Thestudy was conducted according to the following design. Several testswere run to determine in-vivo drug delivery characteristics of therapamycin from the coated balloons.

The first test included expansion of the coated balloons in rabbit iliacarteries. 8 coated balloons were manufactured and tested in 4 rabbits.Four of the coated balloons were inflated in predicted arteries (rightiliac) for 60 seconds, and four of the coated balloons were inflated innon-dilated arteries (left iliac) for 60 seconds. The amount of drug(sirolimus) found in the arterial tissue at the site of expansion wasdetermined. The following table indicates the results of the testing ofthese arteries for sirolimus concentration in arterial tissue and totalamount of sirolimus in each artery. Drug coated balloons in right iliacarteries were inflated/deflated about 10-20 min before sacrifice. Drugcoated balloons in left iliac arteries were inflated/deflated about 5-15min before sacrifice.

Total Sirolimus Average per Artery Sirolimus Average Iliac Artery(ng/mg) SD (μg) SD Right Iliac (denuded) (n = 4) 178.3 32.1 5.4 1.1 LeftIliac (uninjured) (n = 4) 216.1 122.4 3.9 1.7 Combined Right + LeftIliac 197.2 85.3 4.7 1.6 Arteries (n = 8)

The following table indicates the raw data of the testing of these samearteries for the total amount of sirolimus in each artery. It alsoindicates a calculated transfer efficiency of sirolimus to the rabbitiliac arteries and the estimated time that the artery was exposed toblood ow. The percent (%) sirolimus transferred to the artery wascalculated using an estimated total amount of sirolimus on the balloon.The estimated total amount of sirolimus on the balloon which was basedon the batch average total amount of sirolimus coated on the same batchof balloons as the test sample balloon as determined by UV-Viscometrictesting of the balloon. The estimated time that the artery was exposedto blood flow was the amount of time between balloon inflation and theballoon testing, and/or the time between balloon inflation and until theanimal was sacrificed and the artery extracted for testing by HPLC forcontent of drug.

Estimated Total % Time Artery Sirolimus Sirolimus Exposed to Balloon perArtery Transferred Blood Flow Rabbit # # (μg) to Artery (min) #1 RightIliac Artery N185 5.0 7.76% 20 #1 Left Iliac Artery N157 3.2 5.58% 15 #2Right Iliac Artery N164 7.0 12.62% 10 #2 Left Iliac Artery N167 5.08.98% 5 #3 Right Iliac Artery N175 5.1 9.17% 10 #3 Left Iliac ArteryN178 1.8 2.88% 5 #4 Right Iliac Artery N191 4.5 7.59% 15 #4 Left IliacArtery N117 5.7 7.95% 10 Tracking Average — 4.7 7.8% — SD — 1.6 2.8% —

The following table indicates the blood concentrations of sirolimus(whole blood) taken from the animals used in this test. A baselineconcentration of sirolimus was taken prior to exposure to the coatedballoon for each animal, that is, taken before balloon inflation. Thewhole blood samples were taken 5 to 15 minutes after the second balloonwas inflated in each animal, since two coated balloons were delivered toeach animal in this test. The results indicated in the table below,therefore, indicate the cumulative whole blood Sirolimus concentrationfrom the inflation of 2 drug coated balloons per animal. The totalsirolimus in blood is based on 56 mL of blood per kg (i.e. per kg weightof the rabbit tested).

Extraction Est. Total Sirolimus Rabbit # Conc. (ng/mL) in Blood (μg) #1Baseline Below Quality Level — #2 Baseline Below Quality Level — #3Baseline Below Quality Level — #4 Baseline Below Quality Level — #1 (15min) 11.4 2.7 #2 (5 min) 30.8 8.2 #3 (5 min) 22.2 5.9 #4 (10 min) 19.34.8 Average (5-15 min) 20.9 5.4 SD 8.0 2.3

The following table indicates the concentrations of sirolimus on eachballoon used in this test following the test itself, to indicate thepercent (%) of sirolimus lost following the test procedure. As notedabove, each of the balloons was tracked to the respective artery, andinflated for 60 seconds (1 minute), then deflated and removed from theanimal and tested for the percent of Sirolimus remaining on the balloon.The percent (%) sirolimus lost is based on the amount of sirolimusremaining on the balloon following the test and the total amount ofSirolimus coated on the balloon which is estimated from the balloonbatch average as tested using UV-Viscometric methods. The variableswhich contribute to the amount (or percent) of sirolimus lost includethe following: Balloon insertion into iliac (via jugular+aorta); Bloodflow; Pleat/Fold/Sheath methods and procedures: −10% lost duringshipping; and/or Balloon inflation/contact with artery wall.

Total Sirolimus per Balloon % Sirolimus Balloon ID (μg) Lost Rabbit #1RIA Balloon N185 13.2 79.3% Robbie #1 LIA Balloon N157 17.3 69.9% Rabbit#2 RIA Balloon N164 4.8 91.5% Rabbit #2 LIA Balloon N167 11.7 79.1%Rabbit #3 RIA Balloon N175 16.0 71.4% Rabbit #3 LIA Balloon N178 14.777.0% Rabbit #4 RIA Balloon N191 9.6 83.6% Rabbit #4 LIA Balloon N11714.9 79.1% Tracking Average 12.8 78.9% SD 4.0 6.8%

In another test, tracking studies were conducted. The test comprisestracking 4 coated balloons to the aorta of a rabbit. Each of 4 coatedballoons was inserted, tracked to the aorta of the rabbit, and left inthe aorta for 2 minutes without inflating the balloon. Followinginsertion, tracking, and resting the balloon in the aorta for 2 minutes,the catheter including the coated balloon was removed from the animal.

The following table indicates the concentrations of sirolimus on eachballoon used in this test following the test itself, to indicate thepercent (%) of sirolimus lost following the test procedure. The percent(%) sirolimus lost is based on the amount of sirolimus remaining on theballoon following the test and the total amount of sirolimus coated onthe balloon which is estimated from the balloon batch average as testedusing UV-Viscometric methods. The variables which contribute to theamount (or percent) of sirolimus lost include the following: Ballooninsertion into iliac (via jugular+aorta); Blood flow; Pleat/Fold/Sheathmethods and procedures; and/or −10% lost during shipping.

Total Sirolimus per Balloon % Sirolimus Balloon ID (μg) Lost Tracking #1Balloon (N120) 23.6 66.9% Tracking #2 Balloon (N160) 20.8 63.9% Tracking#3 Balloon (N166) 19.0 66.0% Tracking #4 Balloon (N176) 22.0 65.5%Tracking Average 21.3 65.6% SD 2.0 1.3%

Sirolimus quantification was performed on the balloons and blood samplesfrom the previous two tests (as indicated in the “Total Sirolimus perBalloon (ug)” columns of the previous two tables, and as indicated inthe blood concentration table generally). That is, sirolimus content wasdetermined from the 8 balloons inflated in rabbit iliac arteries, the 4balloons tracked to but not inflated in rabbit aorta, and the 8 wholeblood samples (2 samples/rabbit). The liver, kidney, spleens, hearts andlungs were stored (80° C.) for later drug analysis.

In summary, the tests performed in this Example indicate the following:197.2±85.3 ng/mg of Sirolimus embedded in artery walls. The Efficiencyof Sirolimus transferred from balloons to artery walls was 7.8±2.8%>.The amount of sirolimus washed away into circulation was 5.4±2.3 μg.Following inflation in arteries, 78.9±6.8%> of the sirolimus coated onthe balloon was removed from the balloon. Prior to inflation in thearteries, 65.6±1.3% of the sirolimus coated on the balloon was removedfrom the balloon. For reference, 50-100 μg of sirolimus was coated oneach balloon. From 1%) to 5% of the drug (sirolimus) was transferred tothe artery, 1 ng of sirolimus per mg tissue was found during the testingas described in this example.

Example 4: In Vivo Delivery of Rapamycin from Coated Balloons

Binding agents may be incorporated into the coating to improve activeagent retention in the artery. Example binding agents include cationicagents and/or positively charged molecules. An example binding agent maybe a surfactant. Other agents may also and/or alternatively be used.Binding agents may include, for non-limiting example, at least one of:Polyarginine, Polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethylcellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI(Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB(Dimethylditetradecylammonium bromide). In some embodiments of thedevices, coatings and/or methods provided herein the coating comprises apositive surface charge on a surface of the coating configured tocontact the treatment site.

In some embodiments the surfactant comprises at least one of a primaryamine having pH<10, and a secondary amine having pH<4. In someembodiments surfactant comprises octenidine dihydrochloride. In someembodiments the surfactant comprises a permanently charged quaternaryammonium cation. In some embodiments the permanently charged quaternaryammonium cation comprises at least one of: an Alkyltrimethylammoniumsalt such as cetyl trimethylammonium bromide (CTAB), hexadecyl trimethylammonium bromide, cetyl trimethylammonium chloride (CTAC):Cetylpyridinium chloride (CPC); Polyethoxylated tallow amine (POEA);Benzalkonium chloride (BAC); Benzethonium chloride (BZT);5-Bromo-5-nitro-1,3-dioxane; Dimethyldioctadecylammonium chloride; andDioctadecyldimethylammonium bromide (DODAB). In some embodiments thesurfactant comprises at least one of: didodecyldimethylammonium bromide(DMAB), linear isoform Polyethylenimine (linear PEI), Branched Low MWPolyethylenimine (PEI) (of about <25 KDa). Branched Low MWPolyethylenimine (PEI) (of about <15 KDa), Branched Low MWPolyethylenimine (PEI) (of about <10 KDa), Branched High MWPolyethylenimine (of about >/=25 KDa), Poly-L-Arginine (average ornominal MW of about 70,000 Da), Poly-L-Arginine (average or nominal MW>about 50,000 Da), Poly-L-Arginine (average or nominal MW of about 5,000to about 15,000 Da), Poly-L-Lysine (average or nominal MW of about28,200 Da), Poly-L-Lysine (average or nominal MW of about 67,000 Da),Poly Histidine, Ethylhexadecyldimethylammonium Bromide, DodecyltrimethylAmmonium Bromide, Tetradodecylammonium bromide, DimethylditetradecylAmmonium bromide, Tetrabutylammonium iodide, DEAE-Dextran hydrochloride,and Hexadimethrine Bromide. In some embodiments, the molecular weight ofthe binding agent is controlled. In some embodiments, the average sizeof the binding agent is controlled.

In some embodiments of the devices, coatings and/or methods providedherein the binding agent and the active agent are mixed and depositedtogether on the device. In some embodiments, the active agent andbinding agent are lyophilized prior to deposition on the device. In someembodiments dry particles of the active agent and binding agent aregenerated in another manner familiar to one of skill in the art and thencoated on the balloon or other medical device as described herein, suchas by an eSTAT coating process. In some embodiments of the devices,coatings and/or methods provided herein the surfactant is deposited on aballoon after the active agent is deposited thereon.

The positive surface charge of the coating may be about 20 mV to about40 mV. The positive surface charge may be at least one of: at leastabout 1 mV, over about 1 mV, at least about 5 mV, at least about 10 mV,about 10 mV to about 50 mV, about 20 mV to about 50 mV, about 10 mV toabout 40 mV, about 30 mV to about 40 mV, about 20 mV to about 30 mV, andabout 25 mV to about 35 mV. In some embodiments the average molecularweight of the binding agent is controlled. For example, Polyarginine mayhave an average molecular weight of 70 kDa, 5-15 kDa, another controlledmolecular weight, or a combination thereof. In some embodiments themolecular weight of the binding agent is controlled. For example, insome embodiments, Polyarginine is the binding agent and at least 75% ofthe Polyarginine as is 70 kDa, 5-15 kDa, or another controlled molecularweight. In some embodiments, Polyarginine is the binding agent and atleast 50% of the Polyarginine as is 70 kDa, 5-15 kDa, or anothercontrolled molecular weight. In some embodiments, Polyarginine is thebinding agent and at least 90% of the Polyarginine as is 70 kDa, 5-15kDa, or another controlled molecular weight. In some embodiments,Polyarginine is the binding agent and at least 95% of the Polyarginineas is 70 kDa, 5-15 kDa, or another controlled molecular weight. In someembodiments, Polyarginine is the binding agent and at least 98% of thePolyarginine as is 70 kDa, 5-15 kDa, or another controlled molecularweight. In some embodiments, Polyarginine is the binding agent and atleast 99% of the Polyarginine as is 70 kDa, 5-15 kDa, or anothercontrolled molecular weight.

In some embodiments, the size of the active agent in the coating iscontrolled in order to improve drug retention in the artery. Fornon-limiting example, in the case of sirolimus as an active agent, thesirolimus may have an average size (mean diameter) of at least one of:1.5 μηι, 2.5 μιη, 645 nm, 100-200 nm, another controlled size, or acombination thereof. In some embodiments, the active agent is sirolimusand wherein the sirolimus has a median size of at least one of: 1.5 μηι,2.5 μηι, 645 nm, 100-200 nm, another controlled size, or a combinationthereof. In some embodiments, the active agent is sirolimus and whereinthe sirolimus has an average size (mean diameter) of at least one of:about 1.5 μηι, about 2.5 μιη, about 645 nm, about 100-200 nm, anothercontrolled size, or a combination thereof. In some embodiments, theactive agent is sirolimus and wherein the sirolimus has a median size ofat least one of: about 1.5 μηι, about 2.5 μιη, about 645 nm, about100-200 nm, another controlled size, or a combination thereof. In someembodiments the size of the active agent is controlled. For example, insome embodiments, sirolimus is the active agent and at least 75% of thesirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm, or anothercontrolled size. In some embodiments, sirolimus is the active agent andat least 50% of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200nm, or another controlled size. In some embodiments, sirolimus is theactive agent and at least 90% of the sirolimus as is 1.5 μιη, 2.5 μιη,645 nm, 100-200 nm, or another controlled size. In some embodiments,sirolimus is the active agent and at least 95% of the sirolimus as is1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm, or another controlled size. Insome embodiments, sirolimus is the active agent and at least 98% of thesirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm, or anothercontrolled size. In some embodiments, sirolimus is the active agent andat least 99% of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200nm, or another controlled size. The active agent may be, on average, atleast one of: at most 5 microns, over 1 micrometer, between 1 micrometerand 5 micrometers, about 1.5 micrometers on average, and about 2.5micrometers on average.

In some embodiments, the ratio of the active agent to the binding agentis controlled. In some embodiments, the ratio of active agent to bindingagent is 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:20, 2:1, 3:1, 4:1, 5:1, 10:1,15:1, 20:1, 3:2, 2:3, 5:2, 5:3, 2:5, 3:5, or another controlled ratio.

In some embodiments, the coating may comprise nanoparticles, and thenanoparticles may comprise an active agent and a polymer.

Multiple coating formulations were coated on balloons 3.0×18 or 3.0×17balloons of GHOST Rapid Exchange (Rx) Catheters and delivered in rabbitsto their iliac arteries. The arterial tissue of the rabbits wasextracted at certain time points up to 72 hours and the amount of drugfound in the arterial tissue was determined by methods known to one ofskill in the art, such as by HPLC methods testing the arterial tissue orby UV-Viscometric methods looking at loss of coating or agent during theprocedure, expressed in ng drug (Sirolimus) per mg of tissue, indicatedin the following table (sample sire indicated therein).

5 minutes 24 hours 72 hours Formulation Sirolimus Sirolimus SirolimusComposition Concentration (ng/mg) Concentration (ng/mg) Concentration(ng/mg) F1 127.9 ± 80.2 (n = 20) 0.8 ± 0.9 (n = 12) N/A F2 N/A 10.4 ±14.7 (n = 2) N/A F3 39.0 ± 11.6 (n = 8) 25.2 ± 20.2 (n = 10) 4.7 ± 3.7(n = 7) F4 90.6 ± 59.1 (n = 4) 1.3 ± 1.9 (n = 2) N/A F5 6.6 ± 2.1 (n =4) 15.2 ± 27.6 (n = 6) BQL (n = 4) F6 226.0 ± 22.6 (n = 2) 5.4 ± 7.6 (n= 2) N/A F7 97.2 ± 54.7 (n = 4) 40.5 ± 25.0 (n = 6) 2.7 ± 1.7 (n = 4) F8N/A BQL (n = 2) N/A F9 N/A BQL (n = 2) N/A F10 100.5 ± 17.6 (n = 4) 28.4± 10.9 (n = 6) 10.2 ± 5.6 (n = 4) F11 92.4 ± 18.9 (n = 4) 6.4 ± 11.7 (n= 6) 3.9 ± 5.7 (n = 4) F12 N/A BQL (n = 2) N/A F13A N/A BQL (n = 2) N/AF13B 74.2 ± 13.1 (n = 4) 14.0 ± 11.7 (n = 6) 0.9 ± 1.7 (n = 4) F13C N/ABQL (n = 2) N/A F13D N/A 53.0 ± 5.5 (n = 2) N/A F14A N/A BQL (n = 2) N/AF14B N/A BQL (n = 2) N/A F14C Unable to make formulation F14D N/A BQL (n= 2) N/A F15 114.7 ± 66.2 (n = 4) 108.2 ± 119.8 (n = 4) 46.5 ± 46.1 (n =4) F16 73.7 ± 38.5 (n = 4) N/A BQL (n = 4) F17 404.5 ± 96.0 (n = 4) N/A0.9 ± 1.1 (n = 4) F18 191.3 ± 40.0 (n = 4) N/A 1.4 ± 2.8 (n = 4)

The results were calculated as total amount of sirolimus extracted inthe artery, as indicated in the following table:

5 minutes 24 hours 72 hours Formulation Sirolimus Sirolimus SirolimusComposition amount (μg) amount (μg) amount (μg) F1 4.7 ± 1.6 (n = 8) — —F1 (2^(nd) lot) 5.9 ± 1.6 (n = 12) 0.1 ± 0.1 (n = 12) — F2 — 0.4 ± 0.6(n = 2) — F3 3.0 ± 1.5 (n = 6) 0.8 ± 0.5 (n = 8) 0.2 ± 0.1 (n = 6) F3(2^(nd) lot) 1.0 ± 0.4 (n = 2) 1.2 ± 1.6 (n = 2) 1.0 (n = 1) F4 4.5 ±3.2 (n = 4) 0.07 ± 0.1 (n = 2) — F5 0.4 ± 0.2 (n = 4) 0.6 ± 1.0 (n = 6)BQL (n = 4) F6 8.8 ± 1.2 (n = 2) 0.2 ± 0.2 (n = 2) — F7 6.2 ± 3.7 (n =4) 2.1 ± 1.3 (n = 6) 0.2 ± 0.1 (n = 4) F8 — BQL (n = 2) — F9 — BQL (n =2) — F10 2.0 ± 0.4 (n = 4) 1.0 ± 0.8 (n = 6) 0.2 ± 0.1 (n = 4) F11 2.3 ±0.5 (n = 4) 0.3 ± 0.5 (n = 6) 0.1 ± 0.1 (n = 4) F12 — BQL (n = 2) — F13A— BQL (n = 2) — F13B 2.2 ± 0.4 (n = 4) 0.4 ± 0.3 (n = 6) 0.02 ± 0.03 (n= 4) F13C — BQL (n = 2) — F13D — 0.8 ± 0.2 (n = 2) — F14A — BQL (n = 2)— F14B — BQL (n = 2) — F14D — BQL (n = 2) — F15 4.8 ± 0.6 (n = 4) 2.0 ±1.9 (n = 4) 1.2 ± 1.0 (n = 4) F16 2.2 ± 0.8 (n = 4) — BQL (n = 4) F179.4 ± 2.7 (n = 4) — 0.02 ± 0.03 (n = 4) F18 4.4 ± 0.9 (n = 4) — 0.03 ±0.07 (n = 4)

Certain formulations were selected for additional analysis, and theirtest results were normalized for the balloon length and the arterysegment sire extracted. The following results were found for theseselected formulations:

Formulation 5 minutes- Sirolimus 24 hours- Sirolimus 72 hours- SirolimusComposition Concentration (ng/mg) Concentratio (ng/mg) Concentration(ng/mg) F1 278.5 ± 112.2 (n = 20) 2.3 ± 2.6 (n = 12) N/A F3 97.1 ± 49.3(n = 8) 60.1 ± 39.4 (n = 10) 11.9 ± 10.7 (n = 7) F5 19.7 ± 6.4 (n = 4)45.5 ± 82.9 (n = 6) BQL (n = 4) F7 291.5 ± 164.0 (n = 4) 121.5 ± 75.0 (n= 6) 8.0 ± 5.1 (n = 4) F10 167.5 ± 29.4 (n = 4) 58.8 ± 33.3 (n = 6) 17.1± 9.3 (n = 4) F11 153.9 ± 31.4 (n = 4) 17.1 ± 34.8 (n = 6) 6.5 ± 9.5 (n= 4) F13B 130.9 ± 23.2 (n = 4) 24.7 ± 20.6 (n = 6) 1.5 ± 3.0 (n = 4) F15202.5 ± 116.8 (n = 4) 190.9 ± 211.5 (n = 4) 82.0 ± 81.3 (n = 4) F16130.0 ± 67.9 (n = 4) N/A BQL (n = 4) F17 713.8 ± 169.5 (n = 4) N/A 1.6 ±1.9 (n = 4) F18 337.5 ± 70.6 (n = 4) N/A 2.5 ± 5.0 (n = 4)

In the rabbit arterial and blood tests noted in this example, thefollowing coating details and formulations were used.

-   -   F1 (Formulation 1) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and Sirolimus having an average size of 2.5        μιη.    -   F2 (Formulation 2) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1 ratio of Sirolimus having an        average size of 2.5 μιη {acute over (ι)}o Polyarginine 70 kDa.    -   F3 (Formulation 3) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 1.5 μιη or 2.5 μιη {acute over (ι)}o        Polyarginine 70 kDa.    -   F4 (Formulation 4) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 2.5 μιη{acute over (ι)}o DEAE-Dextran        (Diethylaminoethyl cellulose-Dextran).    -   F5 (Formulation 5) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1 ratio of Sirolimus having an        average size of 2.5 μιη and DMAB (Didodecyldimethylammonium        bromide).—F6 (Formulation 6) comprised PLGA i.e. about 50:50        Lactic acid:Glycolic acid, and a 10:1 ratio of Sirolimus having        an average size of 2.5 μιη and DMAB (Didodecyldimethylammonium        bromide). F7 (Formulation 7) comprised PLGA i.e. about 50:50        Lactic acid:Glycolic acid, and a 10:1 ratio of Sirolimus having        an average size of 2.5 μιη and PEI (Polyethyleneimine).    -   F8 (Formulation 8) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 2.5 μιη and TAB (Tetradodecylammonium bromide).    -   F9 (Formulation 9) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 2.5 μιη and DMTAB (Dimethylditetradecylammonium        bromide).    -   F10 (Formulation 10) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1:1 ratio of Sirolimus having an        average size of 2.5 μιη to Polyarginine 70 kDa to PEI        (Polyethyleneimine).    -   F11 (Formulation 11) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1:1 ratio of Sirolimus having an        average size of 2.5 μιη to TAB (Tetradodecylammonium bromide to        DEAE-Dextran (Diethylaminoethyl cellulose-Dextran).    -   F12 (Formulation 12) comprised PLGA Nanospheres (130 nm) where        the PLGA is 50:50 Lactic acid:Glycolic acid, and 6.3% Sirolimus.    -   F13A (Formulation 13A) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and Sirolimus having an average size of 645        nm.    -   F13B (Formulation 13B) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 645 nm to Polyarginine 70 kDa. F13C (Formulation        13C) comprised PLGA i.e. about 50:50 Lactic acid:Glycolic acid,        and a 1:1 ratio of Sirolimus having an average size of 645 nm to        DMAB (Didodecyldimethylammonium bromide).    -   F13D (Formulation 13D) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 645 nm to PEI (Polyethyleneimine).    -   F14A (Formulation 14A) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and Sirolimus having an average size of        100-200 nm.    -   F14B (Formulation 14B) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 100-200 nm to Polyarginine 70 kDa.    -   F14C (Formulation 14C) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 1:1 ratio of Sirolimus having an        average size of 100-200 nm to DMAB (Didodecyldimethylammonium        bromide). Note that this formulation was not able to be made,        therefore, no animal study results were obtained.    -   F14D (Formulation 14D) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 100-200 nm to PEI (Polyethyleneimine).    -   F15 (Formulation 15) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 1.5 μιη to Polyarginine 5-15 kDa.    -   F16 (Formulation 16) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 1.5 μιη to Polyarginine 9-L-pArg.    -   F17 (Formulation 17) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 645 nm to Polyarginine 5-15 kDa.    -   F18 (Formulation 18) comprised PLGA i.e. about 50:50 Lactic        acid:Glycolic acid, and a 10:1 ratio of Sirolimus having an        average size of 645 nm to Polyarginine 9-L-pArg.

With the exception of F12, all methods comprised using an RESS processfor coating the PLGA on the balloon, and using an eSTAT process forcoating the Sirolimus and the positive charged molecule to the balloon.The general process for coating was 1) Polymer coat by RESS processes,2) Sirolimus and binding agent coat (or sirolimus alone, if there was nobinding agent used in the formulation e.g., 14A) by eSTAT processes, 3)sinter the coated balloon. The binding agent (i.e. charged particle,surfactant, and/or cationic particle) was part of the Sirolimus coatingstep wherein the balloon was coated with both the Sirolimus and thebinding agent using an eSTAT process. Formulation 12 was coated on theballoon using only an eSTAT or an RESS process and a sinter step.

The sirolimus was mixed with the binding agent (e.g. the surfactant, thecationic particle, the charged molecule, for non-limiting example) ifpresent in the particular formulation in the following manner. Theprocess may be adapted to different binding agents and different activeagents, however, it is described herein as used with respect tosirolimus and the binding agents which were surfactants in theformulations noted in this example. Lyophilisation or “freeze drying”processed produced a dry powder of associated drug and binding agent(e.g. surfactant) suitable for depositing onto balloons via the eSTATmethod. Other processes familiar to one of skill in the art may be usedas an alternative to lyophilisation in order to associate the drug andbinding agent in a form suitable for deposition on the balloons via amethod described herein. In this example, rapamycin (sirolimus) wassuspended in water with a binding agent to coat the sirolimus withbinding agent. The well-suspended sirolimus and binding agent solutionwas frozen, retaining the sirolimus and binding agent assembly, and thewater was removed by sublimation to produce the dry sirolimus andbinding agent material.

A pre-lyophilisation set of steps may be used in the process of creatingthe dried sirolimus and binding agent solution for use in the eSTATcoating process. The solution created thereby may be used in a freezedryer. The desired quantity of drug (e.g. sirolimus) and binding agentwere weighed out into a 100 mL Schott bottle. Then 50 mL of water isadded, in increments of 10 mL, to the Schott bottle. During eachincrement the solution is mixed with a stir rod to insure the sirolimusis being wetted. After the 50 mL is added the solution is sonicated in abath sonicator (Branson 1510) for 1 hr. In the final pre-lyophilisationstep, the well-suspended solution is carefully transferred to a 50 mLconical centrifuge tube using a plastic pipette; unsuspended sirolimusand/or binding agent particles (typically found floating on the surfaceof the suspension, are not transferred. Note: the efficiency of thesirolimus suspension by the binding agent affects the actual sirolimusto surfactant ratio of the transferred solution and the final recoveredpowder, often changing it from the initial sirolimus and binding agentratio weighed out.

The Lyophilisation steps may be as follows: The recovered suspension inthe 50 mL centrifuge tube is immersed in liquid nitrogen until thesolution is completely frozen. Parafilm is used to cover the opening ofthe tube containing the frozen suspension, while perforations are madein the film to allow escape of the vapor phase water. The tubecontaining the frozen sample is loaded into a freeze dryer containmentvessel and the vessel is attached to one of the freeze dryer stations.The switch above the nozzle for the loaded station is activated to beginthe process. The lyophilisation step is complete when all of the frozenmoisture is visibly absent from the tube. The sample, which may exist asa xerogel following lyophilisation, is easily converted to afree-flowing dry powder by shaking or stirring when the process iscomplete. It usually takes 1-2 days for a sample prepared as describedabove to complete the lyophilisation step, Note: the freeze-drier mayneed to be periodically be defrosted to remove the accumulated moisturefrom the samples in order to work effectively.

The following steps were taken to make the sirolimus and binding agentdry solution in the eSTAT coating process of the balloons (which hadbeen pre-coated using an RESS process with PLGA as noted elsewhereherein). Measure out required quantities of sirolimus and binding agentinto a 100 mL Schott bottle. Add 50 mL of water, in increments of 10 mL,to the Schott bottle. During each increment use a stir rod to mix thesirolimus and binding agent solution. After 50 mL of water is added,sonicate the solution for 1 hr. After sonication use a plastic pipetteto transfer the suspended solution to a 50 mL centrifuge tube. Avoidtransfer of any unsuspended sirolimus and binding agent particles. Place50 mL conical tube (without lid) in liquid nitrogen until solution iscompletely frozen. Cover the top of the conical tube with parafilm andmake holes in film for water to travel through. Seal the 50 mL conicalbottle in the lyophilisation vessel and connect the vessel to a freezedryer nozzle station. Turn switch above the nozzle to evacuate the airfrom the vessel. Keep sample on the freeze-drier until all water hasbeen removed (typically 1-2 days)

Rabbit Blood Concentration results follow. The amount of drug as aconcentration per mL of blood was determined for several formulations,as indicated in the following table.

Sirolimus in whole blood (ng/mL) Formulation 5 min 24 hours 72 hours F120.9 ± 8.0 (n = 4) N/A N/A F1 (2^(nd) lot) 5.7 ± 1.6 (n = 6) BQL (n = 6)N/A F2 N/A BQL (n = 1) N/A F3 7.7 ± 3.7 (n = 3) 0.8 ± 0.7 (n = 4) BQL (n= 3) F3 (2^(nd) lot) 5.5 (n = 1) BQL (n = 1) BQL (n = 1) F4 N/A BQL (n= 1) N/A F5 0.99 ± 0.1 (n = 2) BQL (n = 3) BQL (n = 2) F6 N/A 2.72 (n= 1) N/A F7 11.2 ± 3.4 (n = 2) 1.7 ± 0.3 (n = 3) 1.3 ± 0.9 (n = 2) F8N/A BQL (n = 1) N/A F9 N/A 2.06 (n = 1) N/A F10 BQL (n = 2) 0.36 ± 0.6(n = 3) BQL (n = 2) F11 10.1 ± 0.2 (n = 2) BQL (n = 3) BQL (n = 2) F12N/A BQL (n = 1) N/A F13A N/A 1.13 (n = 1) N/A F13B 6.4 ± 3.1 (n = 2) 1.0± 0.9 (n = 3) BQL (n = 2) F13C N/A BQL (n = 1) N/A F13D N/A 2.99 (n = 1)N/A F14A N/A BQL (n = 1) N/A F14B N/A BQL (n = 1) N/A F14D N/A BQL (n= 1) N/A F15 5.7 ± 3.2 (n = 2) 1.8 ± 0.01 (n = 2) BQL (n = 2) F16 76.8 ±89.4 (n = 2) N/A BQL (n = 2) F17 25.6 ± 1.3 (n = 2) N/A BQL (n = 2) F1823.5 ± 3.3 (n = 2) N/A 0.5 ± 0.8 (n = 2)The amount of drug as a total amount found in the arterial tissue wasdetermined for several formulations, as indicated in the followingtable.

Sirolimus in whole blood (μg) Formulation 5 min 24 hours 72 hours F1 5.4± 2.3 (n = 4) N/A N/A F1 (2^(nd) lot) 1.0 ± 0.3 (n = 6) BQL (n = 6) N/AF2 N/A BQL (n = 1) N/A F3 1.7 ± 0.6 (n = 3) 0.1 ± 0.1 (n = 4) BQL (n =3) F3 (2^(nd) lot) 1.2 (n = 1) BQL (n = 1) BQL (n = 1) F4 N/A BQL (n= 1) N/A F5 0.18 ± 0.2 (n = 2) BQL (n = 3) BQL (n = 2) F6 — 0.4 (n = 1)N/A F7 1.9 ± 0.6 (n = 2) 0.3 ± 0.1 (n = 3) 0.25 ± 0.01 (n = 2) F8 N/ABQL (n = 1) N/A F9 N/A 0.3 (n = 1) N/A F10 BQL (n = 2) 0.1 ± 0.1 (n = 3)BQL (n = 2) F11 2.0 ± 0.05 (n = 2) BQL (n = 3) BQL (n = 2) F12 N/A BQL(n = 1) N/A F13A N/A 0.2 (n = 1) N/A F13B 1.3 ± 0.7 (n = 2) 0.2 ± 0.2 (n= 3) BQL (n = 2) F13C N/A BQL (n = 1) N/A F13D N/A 0.6 (n = 1) N/A F14AN/A BQL (n = 1) N/A F14B N/A BQL (n = 1) N/A F14D N/A BQL (n = 1) N/AF15 1.2 ± 0.7 (n = 2) 0.4 ± 0.0 (n = 2) BQL (n = 2) F16 18.7 ± 21.9 (n =2) N/A BQL (n = 2) F17 6.2 ± 0.3 (n = 2) N/A BQL (n = 2) F18 5.5 ± 0.6(n = 2) N/A 0.12 ± 0.17 (n = 2)

The various formulations had the following average amount of sirolimuscoated on each of the balloons tested in the rabbit arteries. These wereaverage amounts of drug found on sample balloons coated according to thesame procedures noted herein and from the same lots and batches as thosetested in the rabbits as noted above.

Formulation Sirolimus Coated on Balloons (μg) F1 64.52 ± 8.73 F1 (2^(nd)lot) 63.40 ± 2.89 F2 41.05 ± 7.17 F3  89.54 ± 19.61 F3 (2^(nd) lot)128.71 ± 26.86 F4 115.12 ± 16.92 F5 68.49 ± 4.73 F6 316.95 ± 82.66 F7165.25 ± 17.47 F8  97.19 ± 16.46 F9 218.86 ± 26.73 F10  65.38 ± 24.45F11 170.66 ± 14.30 F12  74.20 ± 15.77 F13A 134.23 ± 17.03 F13B 144.63 ±51.84 F13C  55.46 ± 13.14 F13D 105.31 ± 16.02 F14A  83.10 ± 15.19 F14B175.96 ± 78.30 F14D  77.50 ± 31.02 F15 106.53 ± 22.55 F16 75.84 ± 5.98F17 197.64 ± 15.89 F18 196.43 ± 45.89

Following expansion of the balloons in the rabbit arteries, each of theballoons was removed from the animal and the residual sirolimus on eachballoon was determined. Using the 5 minute data as an indication of theamount (and therefore percent) of sirolimus transferred to the artery,and using the amount of drug remaining on the balloon following theprocedure, and using the average amount of drug on balloons of the samebatch as an estimate of the total amount of drug on the original device(see the previous table), the percent of sirolimus transferred to therabbit artery and the total percent of sirolimus released during theentire procedure was determined. The following table summarizes theresults from the formulations tested in this manner.

% Sirolimus Transferred Sirolimus on to Artery (5 min) Balloon Post-From Sirolimus Released % Sirolimus Formulation Deployment (μg) offRespective Balloon Released F1 12.8 ± 4.0 (n = 8) 9.8 ± 3.1% (n = 8)78.9 ± 6.8% (n = 8) F1 (2^(nd) lot) 45.7 ± 7.3 (n = 36) 23.0 ± 8.5% (n =12) 35.9 ± 10.2% (n = 36) F2 6.1 ± 2.7 (n = 2) N/A 85.1 ± 3.6% (n = 2)F3 27.6 ± 9.1 (n = 20) 4.8 ± 1.4% (n = 6) 68.4 ± 15.4% (n = 20) F3(2^(nd) lot) 56.8 ± 15.6 (n = 6) 1.2 ± 0.6% (n = 2) 59.0 ± 8.6% (n = 6)F4 16.0 ± 2.9 (n = 6) 5.1 ± 3.5% (n = 4) 84.9 ± 2.5% (n = 6) F5 5.0 ±2.7 (n = 14) 0.6 ± 0.2% (n = 4) 92.8 ± 3.7% (n = 14) F6 49.4 ± 6.9 (n =4) 3.5 ± 0.2% (n = 2) 84.4 ± 3.7% (n = 4) F7 7.1 ± 3.0 (n = 14) 3.9 ±2.4% (n = 4) 95.7 ± 1.7% (n = 14) F8 20.5 ± 0.1 (n = 2) N/A 78.1 ± 3.8%(n = 2) F9 37.0 ± 4.1 (n = 2) N/A 82.6 ± 0.3% (n = 2) F10 1.4 ± 0.8 (n =14) 4.0 ± 0.3% (n = 4) 98.1 ± 0.8% (n = 14) F11 43.6 ± 11.2 (n = 14) 1.7± 0.4% (n = 4) 74.4 ± 6.9% (n = 14) F12 2.3 ± 0.8 (n = 2) N/A 97.1 ±1.0% (n = 2) F13A 21.6 ± 1.0 (n = 2) N/A 85.0 ± 0.8% (n = 2) F13B 30.4 ±7.4 (n = 14) 3.8 ± 0.6% (n = 4) 76.5 ± 7.2% (n = 14) F13C 2.1 ± 0.1 (n =2) N/A 96.6 ± 0.0% (n = 2) F13D 9.2 ± 2.6 (n = 2) N/A 92.1 ± 2.3% (n =2) F14A 11.6 ± 0.8 (n = 2) N/A 87.5 ± 0.3% (n = 2) F14B 16.4 ± 0.6 (n =2) N/A 91.9 ± 0.8% (n = 2) F14D 1.7 ± 0.1 (n = 2) N/A 98.5 ± 0.1% (n =2) F15 24.9 ± 5.6 (n = 12) 5.3 ± 0.7% (n = 4) 76.4 ± 6.3% (n = 12) F1621.4 ± 3.9 (n = 12) 4.2 ± 1.6% (n = 4) 72.0 ± 4.6% (n = 12) F17 49.3 ±6.9 (n = 12) 6.6 ± 1.9% (n = 4) 74.6 ± 3.6% (n = 12) F18 44.5 ± 8.7 (n =12) 2.5 ± 0.8% (n = 4) 76.4 ± 3.3% (n = 12)

The following summary observations may be made with regard to the Rabbitarterial and blood testing noted in this Example. Formulation 15 has themost drug retention at 72 hours of any other formulation. Formulation 3had a sirolimus retention of 3.9+/−3.4 ng/mg at 72 hours (both lotscombined), and 3.2% of the drug released from the balloons (both lotscombined) was retained in the artery five minutes after expansion of theballoon in the artery. Formulation 13B had a sirolimus retention of0.9+/−1.7 ng/mg at 72 hours, and 3.8% of the drug released from theballoons was retained in the artery five minutes after expansion of theballoon in the artery. Formulation 15 had a sirolimus retention of46.5+/−46.1 ng/mg at 72 hours, and 5.3% of the drug released from theballoons was retained in the artery five minutes after expansion of theballoon in the artery.

In some embodiments of the methods, coatings, or devices providedherein, the coating comprises and a 10:1 ratio of the active agent tothe binding agent, wherein the active agent comprises sirolimus whereinthe binding agent comprises Polyarginine. In some embodiments, thesirolimus has an average size of 1.5 μιη or 2.5 μιη. In someembodiments, the Polyarginine average molecular weight is 70 kDa. Insome embodiments, the Polyarginine average molecular weight is 5-15 kDa.In some embodiments, the active agent and the binding agent aredeposited on the balloon together using an eSTAT coating process. Insome embodiments, the active agent and the binding agent are lyophilizedprior to deposition on the balloon. In some embodiments, at least about2 ng/mg of active agent are found in arterial tissue 72 hours afterinflation of the balloon in the artery. In some embodiments, at leastabout 3 ng/mg of active agent are found in arterial tissue 72 hoursafter inflation of the balloon in the artery. In some embodiments, atleast about 5 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 10 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 20 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 30 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery. In some embodiments,at least about 40 ng/mg of active agent are found in arterial tissue 72hours after inflation of the balloon in the artery.

In some embodiments of the methods, coatings, or devices providedherein, in vivo measurement comprises inflating the balloon inside theartery of a porcine for about 1 minute and wherein the amount of activeagent transferred to the artery is measured by UV-Vis evaluation of thecoating remaining on the balloon as determined about five minutes afterinflation of the balloon in the artery. In some embodiments of themethods, coatings, or devices provided herein, in vivo measurementcomprises inflating the balloon inside the artery of a porcine for about1 minute and wherein the amount of active agent transferred to theartery is measured by extracting the artery about five minutes afterinflation of the balloon in the artery and determining the amount ofdrug in the extracted artery using standard methods described hereinand/or known to one of skill in the art. In some embodiments of themethods, coatings, or devices provided herein, in vivo measurementcomprises inflating the balloon inside the artery of a rabbit for about1 minute and wherein the amount of active agent transferred to theartery is measured by UV-Vis evaluation of the coating remaining on theballoon as determined about five minutes after inflation of the balloonin the artery. In some embodiments of the methods, coatings, or devicesprovided herein, in vivo measurement comprises inflating the ballooninside the artery of a rabbit for about 1 minute and wherein the amountof active agent transferred to the artery is measured by extracting theartery about five minutes after inflation of the balloon in the arteryand determining the amount of drug in the extracted artery usingstandard methods described herein and/or known to one of skill in theart.

Provided herein is a method of forming a coating on a medical devicecomprising depositing a polymer on the medical device using an RESSprocess, mixing a binding agent and active agent to create an activeagent-binding agent mixture, lyophilizing the active agent-binding agentmixture and depositing the active agent-binding agent mixture on themedical device using an eSTAT process. In some embodiments, the bindingagent comprises a surfactant.

Pharmacokinetic Studies in Porcine Models:

Formulation 3 (F3) was coated on balloons of 3.0×17 Ghost Rapid Exchange(Rx) Catheters according to the procedures noted above and delivered inporcine to their coronary and mammary arteries. The animals weresacrificed and arterial tissue was extracted at several time points. Theamount of drug found in the coronary arterial tissue was determined andis expressed in ng drug (Sirolimus) per mg of tissue, and is expressedin normalized form, i.e. normalized per mg of tissue and expressed inmicrograms {circumflex over ( )}g) in the following table.

Arterial Total Sirolimus Sirolimus Concentration per Artery Time Point(ng/mg) SD (μg) SD Day 1: Coronary (n = 5) 5.528 4.806 0.3647 0.3056 Day3: Coronary (n = 6) 2.559 2.927 0.1436 0.1402 Day 7: Coronary (n = 5)1.141 1.324 0.0948 0.1375 Day 14: Coronary (n = 5) 0.764 0.858 0.06450.0940 Day 30: Coronary (n = 5) 0.038 0.085 0.0013 0.0029

The amount of drug found in the mammary arterial tissue was determinedand is expressed in ng drug (Sirolimus) per mg of tissue, and isexpressed in normalized form, i.e. normalized per mg of tissue andexpressed in micrograms {circumflex over ( )}g) in the following table.

Arterial Total Sirolimus Sirolimus Concentration per Artery Time Point(ng/mg) SD (μg) SD Day 1: Mammary (n = 5) 2.722 2.931 0.1303 0.1285 Day3: Mammary (n = 4) 0.243 0.386 0.0129 0.0200 Day 7: Mammary (n = 9)0.277 0.648 0.0100 0.0225 Day 14: Mammary (n = 4) 0.105 0.066 0.00580.0037 Day 30: Mammary (n = 9) 0.030 0.090 0.0014 0.0043

A comparison was performed between arterial drug retention in a rabbitversus the porcine model, using the F3 formulation as described above.The comparison indicated that at Day 1, the Rabbit Iliac arteryconcentration of sirolimus was 25.20+/−20.20 in ng sirolimus per mgtissue, or 0.901 μg+/−0.684 μg when normalized by the amount of tissuein the sample (n=7-10). At the same time point at Day 1, the PorcineCoronary artery concentration of sirolimus was 5.528+/−4.806 in ngsirolimus per mg tissue, or 0.365 μg+/−0.306 μg when normalized by theamount of tissue in the sample (n=5-6). At Day 3, the rabbit iliacartery concentration of sirolimus was 4.66+/−3.65 in ng sirolimus per mgtissue, or 0.319 μg+/−0.338 μg when normalized by the amount of tissuein the sample. At the same time point at Day 3, the porcine coronaryartery concentration of sirolimus was 2.559+/−2.927 in ng sirolimus permg tissue, or 0.144 μg+/−0.144 μg when normalized by the amount oftissue in the sample.

Several formulations that were selected for 72-hour testing in therabbit iliac model were submitted for elution testing using a standardelution method. FIG. 1 indicates the Average percent Sirolimus Elutedfrom the balloons at various time points for Formulations F3, F5, andF7. At time 0 days, the F5 is the highest percent elution at about 60%,and the F3 elution is the next highest data point at about 45% elutionat 0 days, whereas F7 is the lowest line throughout all time points, atabout 30%) eluted at 0 days. The line for F5 is the top line of thegraph, eluting the fastest of the three formulations indicated in thegraph, whereas F3 is the middle line of the graph, and F7 eluting theslowest only reaching 100%) elution at about day 13.

The coating may release the active agent into a treatment site over atleast one of: about 3 days, about 5 days, about 1 week, about 1.5 weeks,about 2 weeks, about 14 days, about 3 weeks, about 21 days, about 4weeks, about 28 days, about 1 month, about 1.5 months, about 2 months,at least about 3 days, at least about 5 days, at least about 1 week, atleast about 1.5 weeks, at least about 2 weeks, at least about 14 days,at least about 3 weeks, at least about 21 days, at least about 4 weeks,at least about 28 days, at least about 1 month, at least about 1.5months, at least about 2 months, about 7 to about 14 days, about 14 toabout 21 days, about 14 to about 28 days, about 21 to about 28 days, andabout 7 to about 28 days.

Provided herein is a coated medical device comprising: a medical devicefor delivering encapsulated active agent to a treatment site; and acoating on the medical device comprising the encapsulated active agentwherein the encapsulated active agent comprise active agent encapsulatedin a polymer, and wherein the encapsulated active agent has a positivesurface charge.

Provided herein is a coated medical device comprising: a medical devicefor delivering encapsulated active agent to a treatment site; and acoating on the medical device comprising the encapsulated active agentwherein the encapsulated active agent comprise a polymer that encapsulesat least a portion of an active agent, and wherein the encapsulatedactive agent has a positive surface charge.

In some embodiments, the active agent is not completely encapsulated. Anactive agent (or a portion thereof) need not be completely surrounded inorder to be encapsulated by the polymer. In some embodiments, at least10% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 20%> of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 25% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 30% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 40% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 50% of the surface area of theactive agent is encapsulated in the polymer.

In some embodiments, at least 60% of the surface area of the activeagent is encapsulated in the polymer. In some embodiments, at least 70%of the surface area of the active agent is encapsulated in the polymer.In some embodiments, at least 75% of the surface area of the activeagent is encapsulated in the polymer. In some embodiments, at least 80%of the surface area of the active agent is encapsulated in the polymer.In some embodiments, at least 90% of the surface area of the activeagent is encapsulated in the polymer. In some embodiments, at least 95%of the surface area of the active agent is encapsulated in the polymer.In some embodiments, at least one of: at least 5% of the surface area ofthe active agent is at least partially surrounded by the polymer, atleast 10% of the surface area of the active agent is at least partiallysurrounded by the polymer, at least 15%) of the surface area of theactive agent is at least partially surrounded by the polymer, at least20% of the surface area of the active agent is at least partiallysurrounded by the polymer, at least 25% of the surface area of theactive agent is at least partially surrounded by the polymer, at least30% of the surface area of the active a{circumflex over ( )} *ent is atleast partially surrounded by the polymer, at least 40% of the surfacearea of the active a{circumflex over ( )} *ent is at least partiallysurrounded by the polymer, at least 50% of the surface area of theactive a{circumflex over ( )} *ent is at least partially surrounded bythe polymer₃ at least 60% of the surface area of the active a{circumflexover ( )} *ent is at least partially surrounded by the polymer, at least70% of the surface area of the active a{circumflex over ( )} *ent is atleast partially surrounded by the polymer₃ at least 75% of the surfacearea of the active a{circumflex over ( )} *ent is at least partiallysurrounded by the polymer₃ at least 80% of the surface area of theactive a{circumflex over ( )} *ent is at least partially surrounded bythe polymer, at least 90% of the surface area of the active a{circumflexover ( )} *ent is at least partially surrounded by the polymer, and atleast 95% of the surface area of the active a{circumflex over ( )} *entis at least partially surrounded by the polymer.

Provided herein is a coating for a medical device comprisingencapsulated active agent comprising active agent encapsulated in apolymer, wherein the encapsulated active agent has a positive surfacecharge, and wherein the coating delivers active agent to a treatmentsite over at least about 1 day.

Provided herein is a method of forming a coating on a medical devicecomprising providing encapsulated active agent comprising a polymer andactive agent, wherein the encapsulated active agent have a positivesurface charge, depositing the encapsulated active agent on the medicaldevice. In some embodiments, the coating delivers the active agent tothe treatment site over at least about 1 day.

Provided herein is a method of forming a coating on a medical devicecomprising providing encapsulated active agent comprising a polymer atleast partially encapsulating at least a portion of an active agentwherein the encapsulated active agent has a positive surface charge, anddepositing the encapsulated active agent on the medical device. In someembodiments, the coating delivers the active agent to the treatment siteover at least about 1 day.

Provided herein is a coated medical device comprising: a medical devicefor delivering an active agent to a treatment site; and a coating on thedevice comprising the active agent, wherein the coated medical devicedelivers at least a portion of the coating to the treatment site whichportion releases active agent into the treatment site over at leastabout 1 day.

Provided herein is a coating for a medical device comprising an activeagent, wherein the coating delivers the into a treatment site over atleast about 1 day.

Provided herein is a method of forming coating on a medical device withof an active agent comprising depositing the active agent on the medicaldevice using an eSTAT process.

In some embodiments of the devices, coatings and/or methods providedherein the polymer comprises PLGA. The PLGA may have at least one of: aMW of about 30 KDa and a Mn of about 15 KDa, a Mn of about 10 KDa toabout 25 KDa, and a MW of about 15 KDa to about 40 KDa.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a bioabsorbable polymer. In some embodiments, theactive agent comprises a bioabsorbable polymer. In some embodiments, thebioabsorbable polymer comprises at least one of: Polylactides (PLA);PLGA (poly(lactide-co-glycolide)); Polyanhydrides; Polyorthoesters;Poly(N-(2-hydroxypropyl) methacrylamide); DLPLA—poly(dl-lactide);LPLA—poly(1-lactide); PGA—polyglycolide; PDO—poly(dioxanone);PGA-TMC—poly(glycolide-co-trimethylene carbonate):PGA-LPLA-—poly(1-lactide-co-glycolide);PGA-DLPLA-—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations, copolymers, and derivatives thereof. In some embodiments,the bioabsorbable polymer comprises between 1% and 95% glycolic acidcontent PLGA-based polymer.

In some embodiments of the methods and/or devices provided herein, thepolymer comprises at least one of polycarboxylic acids, cellulosicpolymers, proteins, polypeptides, polyvinylpyrrolidone, maleic anhydridepolymers, polyamides, polyvinyl alcohols, polyethylene oxides,glycosaminoglycans, polysaccharides, polyesters, aliphatic polyesters,polyurethanes, polystyrenes, copolymers, silicones, silicone containingpolymers, polyalkyl siloxanes, polyorthoesters, polyanhydrides,copolymers of vinyl monomers, polycarbonates, polyethylenes,polypropytenes, polylactic acids, polylactides, polyglycolic acids,polyglycolides, polylactide-co-glycolides, polycaprolactones,poly(e-caprolactone)s, polyhydroxybutyrate valerates, polyacrylamides,polyethers, polyurethane dispersions, polyacrylates, acrylic latexdispersions, polyacrylic acid, polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, aliphatic polycarbonatespolyhydroxyalkanoates, polytetrahalooalkylenes, poly(phosphasones),polytetrahalooalkylenes, poly(phosphasones), and mixtures, combinations,and copolymers thereof. The polymers of the present invention may benatural or synthetic in origin, including gelatin, chitosan, dextrin,cyclodextrin, Poly(urethanes), Poly(siloxanes) or silicones,Poly(acrylates) such as [rho]oly(methyl methacrylate), poly(butylmethacrylate), and Poly(2-hydroxy ethyl methacrylate), Poly(vinylalcohol) Poly(olefins) such as poly(ethylene), [rho]oly(isoprene),halogenated polymers such as Poly(tetrafluoroethylene)—and derivativesand copolymers such as those commonly sold as Teflon® products,Poly(vinylidine fluoride), Poly(vinyl acetate), Poly(vinyl pyrrolidone),Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate),Poly(ethylene glycol), Poly(propylene glycol), Poly(methacrylic acid);etc. Suitable polymers also include absorbable and/or resorbablepolymers including the following, combinations, copolymers andderivatives of the following: Polylactides (PLA), Polyglycolides (PGA),PolyLactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl) methacrylamide), Poly(1-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(1-lactide);PDO—poly(dioxanone); PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide):PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

In some embodiments of the methods and/or devices provided herein, thepolymer has a dry modulus between 3,000 and 12,000 KPa. In someembodiments, the polymer is capable of becoming soft after implantation.In some embodiments, the polymer is capable of becoming soft afterimplantation by hydration, degradation or by a combination of hydrationand degradation. In some embodiments, the polymer is adapted totransfer, free, and/or dissociate from the substrate when at theintervention site due to hydrolysis of the polymer.

In some embodiments of the methods and/or devices provided herein, thebioabsorbable polymer is capable of resorbtion in at least one of: about1 day, about 3 days, about 5 days, about 7 days, about 14 days, about 3weeks, about 4 weeks, about 45 days, about 60 days, about 90 days, about180 days, about 6 months, about 9 months, about 1 year, about 1 to about2 days, about 1 to about 5 days, about 1 to about 2 weeks, about 2 toabout 4 weeks, about 45 to about 60 days, about 45 to about 90 days,about 30 to about 90 days, about 60 to about 90 days, about 90 to about180 days, about 60 to about 180 days, about 180 to about 365 days, about6 months to about 9 months, about 9 months to about 12 months, about 9months to about 15 months, and about 1 year to about 2 years.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a microstructure. In some embodiments, particles ofthe active agent are sequestered or encapsulated within themicrostructure. In some embodiments, the microstructure comprisesmicrochannels, micropores and/or microcavities. In some embodiments, themicrostructure is selected to allow sustained release of the activeagent. In some embodiments, the microstructure is selected to allowcontrolled release of the active agent.

In some embodiments of the devices, coatings and/or methods providedherein the coating comprises a positive surface charge. The positivesurface charge may be about 20 mV to about 40 mV. The positive surfacecharge may be at least one of: at least about 1 mV, over about 1 mV, atleast about 5 mV, at least about 10 mV, about 10 mV to about 50 mV,about 20 mV to about 50 mV, about 10 mV to about 40 mV, about 30 mV toabout 40 mV, about 20 mV to about 30 mV, and about 25 mV to about 35 mV.

In some embodiments of the devices, coatings and/or methods providedherein, the w/w percent of active agent in the encapsulated active agentis about 5%. In some embodiments of the devices, coatings and/or methodsprovided herein, the w/w percent of active agent in the encapsulatedactive agent is about 10-25%.

In some embodiments, the encapsulated active agent comprises a polymerat least partially encapsulating at least a portion of an active agentwherein the encapsulated active agent has a positive surface charge. Insome embodiments, the active agent is not completely encapsulated. Anactive agent (or a portion thereof) need not be completely surrounded inorder to be encapsulated by the polymer. In some embodiments, at least10%> of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 20%> of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 25% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 30% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 40% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 50% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 60% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 70% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 75% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 80% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast 90% of the surface area of the active agent is encapsulated in thepolymer. In some embodiments, at least 95% of the surface area of theactive agent is encapsulated in the polymer. In some embodiments, atleast one of: at least 5% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 10% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 15%) of the surface area of the active agent is atleast partially surrounded by the polymer, at least 20% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 25% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 30% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 40% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 50% of the surfacearea of the active agent is at least partially surrounded by thepolymer₃ at least 60% of the surface area of the active agent is atleast partially surrounded by the polymer, at least 70% of the surfacearea of the active agent is at least partially surrounded by thepolymer₃ at least 75% of the surface area of the active agent is atleast partially surrounded by the polymer₃ at least 80% of the surfacearea of the active agent is at least partially surrounded by thepolymer, at least 90% of the surface area of the active agent is atleast partially surrounded by the polymer, and at least 95% of thesurface area of the active agent is at least partially surrounded by thepolymer.

In some embodiments of the devices, coatings and/or methods providedherein, at least a portion of the encapsulated active agent arenanoparticles. At least a portion of the encapsulated active agent maybe at least one of: a spherical shape, a discoidal shape, ahemispherical shape, a cylindrical shape, a conical shape, a nanoreefshape, a nanobox shape, a cluster shape, a nanotube shape, a whiskershape, a rod shape, a fiber shape, a cup shape, a jack shape, ahexagonal shape, an ellipsoid shape, an oblate ellipsoid shape, aprolate ellipsoid shape, a torus shape, a spheroid shape, a taco-likeshape, a bullet shape, a barrel shape, a lens shape, a capsule shape, apulley wheel shape, a circular disc shape, a rectangular disc shape, ahexagonal disc shape, a flying saucer-like shape, a worm shape, aribbon-like shape, and a ravioli-like shape.

The active agent in some embodiments of the devices, coatings and/ormethods provided herein comprises a macrolide immunosuppressive drug.The active agent may be selected from sirolimus, a prodrug, a hydrate,an ester, a salt, a polymorph, a derivative, and an analog thereof. Aportion of the active agent may be in crystalline form.

The active agent may be, on average, at least one of: at most 5 microns,over 1 micrometer, between 1 micrometer and 5 micrometers, about 1.5micrometers on average, and about 2.5 micrometers on average. In someembodiments, the size of the active agent in the coating is controlledin order to improve drug retention in the artery. For non-limitingexample, in the case of sirolimus as an active agent, the sirolimus mayhave an average size (mean diameter) of at least one of: 1.5 μηι, 2.5μg, 645 nm, 10-200 nm, another controlled size, or a combinationthereof. In some embodiments, the active agent is sirolimus and whereinthe sirolimus has a median size of at least one of: 1.5 μηι, 2.5 μιη,645 nm, 100-200 nm, another controlled size, or a combination thereof.In some embodiments, the active agent is sirolimus and wherein thesirolimus has an average size (mean diameter) of at least one of: about1.5 μηι, about 2.5 μιη, about 645 nm, about 100-200 nm, anothercontrolled size, or a combination thereof. In some embodiments, theactive agent is sirolimus and wherein the sirolimus has a median size ofat least one of: about 1.5 μηι, about 2.5 μιη, about 645 nm, about10-200 nm, another controlled size, or a combination thereof. In someembodiments the size of the active agent is controlled. For example, insome embodiments, sirolimus is the active agent and at least 75%) of thesirolimus as is 1.5 μηι, 2.5 μιη, 645 nm, 100-200 nm, or anothercontrolled size. In some embodiments, sirolimus is the active agent andat least 50% of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200nm, or another controlled size. In some embodiments, sirolimus is theactive agent and at least 90%> of the sirolimus as is 1.5 μιη, 2.5 μιη,645 nm, 100-200 nm, or another controlled size. In some embodiments,sirolimus is the active agent and at least 95% of the sirolimus as is1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm, or another controlled size. Insome embodiments, sirolimus is the active agent and at least 98% of thesirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200 nm, or anothercontrolled size. In some embodiments, sirolimus is the active agent andat least 99%> of the sirolimus as is 1.5 μιη, 2.5 μιη, 645 nm, 100-200nm, or another controlled size.

In some embodiments of the devices, coatings and/or methods providedherein the coating delivers the active agent to the treatment site overat least about 1 day. In some embodiments of the devices, coatingsand/or methods provided herein the coating delivers the active agent tothe treatment site over at least one of: about 3 days, about 5 days,about 1 week, about 1.5 weeks, about 2 weeks, about 14 days, about 3weeks, about 21 days, about 4 weeks, about 28 days, about 1 month, about1.5 months, about 2 months, at least about 3 days, at least about 5days, at least about 1 week, at least about 1.5 weeks, at least about 2weeks, at least about 14 days, at least about 3 weeks, at least about 21days, at least about 4 weeks, at least about 28 days, at least about 1month, at least about 1.5 months, at least about 2 months, about 7 toabout 14 days, about 14 to about 21 days, about 14 to about 28 days,about 21 to about 28 days, and about 7 to about 28 days.

In some embodiments of the devices, coatings and/or methods providedherein the treatment site is a vessel wall. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is acoronary artery. In some embodiments of the devices, coatings and/ormethods provided herein the treatment site is bypass graft. In someembodiments of the devices, coatings and/or methods provided herein thetreatment site is a bifurcated lesion. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is asmall coronary lesions (for example, with reference diameter <2.5 mm).In some embodiments of the devices, coatings and/or methods providedherein the treatment site is a peripheral artery. In some embodiments ofthe devices, coatings and/or methods provided herein the treatment siteis vein. In some embodiments of the devices, coatings and/or methodsprovided herein the treatment site is an AV graft. In some embodimentsof the devices, coatings and/or methods provided herein the treatmentsite is an AV fistula. In some embodiments of the devices, coatingsand/or methods provided herein the treatment site is a biliary tract. Insome embodiments of the devices, coatings and/or methods provided hereinthe treatment site is a biliary duct. In some embodiments of thedevices, coatings and/or methods provided herein the treatment site is asinus. In some embodiments of the devices, coatings and/or methodsprovided herein the treatment site is a vein graft.

In some embodiments of the devices, coatings and/or methods providedherein the coating comprises a positive surface charge on a surface ofthe coating configured to contact the treatment site.

In some embodiments of the devices, coatings and/or methods providedherein the encapsulated active agent are micelles.

In some embodiments of the devices, coatings and/or methods providedherein the medical device comprises a balloon. In some embodiments themedical device is a balloon of a balloon catheter.

In some embodiments of the devices, coatings and/or methods providedherein depositing the encapsulated active agent comprises using an eSTATprocess. In some embodiments of the devices, coatings and/or methodsprovided herein depositing a second polymer on the medical devicefollowing depositing the encapsulated active agent on the medicaldevice.

In some embodiments of the methods, coatings or and/or devices providedherein, the coating is formed on the substrate by a process comprisingdepositing a polymer and/or the active agent by an RESS. e-RESS, ane-SEDS, or an e-DPC process. In some embodiments of the methods and/ordevices provided herein, wherein the coating is formed on the substrateby a process comprising at least one of: depositing a polymer by anRESS, e-RESS, an e-SEDS, or an e-DPC process, and depositing thepharmaceutical agent by an e-RESS, an e-SEDS, eSTAT, or an e-DPCprocess. In some embodiments of the methods and/or devices providedherein, the coating is formed on the substrate by a process comprisingat least one of: depositing a polymer by an RESS, e-RESS, an e-SEDS, oran e-DPC process, and depositing the active agent by an eSTAT. e-RESS,an e-SEDS, or an e-DPC process. In some embodiments, the process offorming the coating provides improved adherence of the coating to thesubstrate prior to deployment of the device at the intervention site andfacilitates dissociation of the coating from the substrate at theintervention site. In some embodiments, the coating is formed on thesubstrate by a process comprising depositing the active agent by aneSTAT, e-RESS, an e-SEDS, or an e-DPC process without electricallycharging the substrate. In some embodiments, the coating is formed onthe substrate by a process comprising depositing the active agent on thesubstrate by an e-RESS, an e-SEDS, or an e-DPC process without creatingan electrical potential between the substrate and a coating apparatusused to deposit the coating.

In some embodiments of the devices, coatings and/or methods providedherein the second polymer comprises PLGA. The PLGA may have at least oneof: a MW of about 30KDa and a Mn of about 15 KDa, a Mn of about 10 KDato about 25 KDa, and a MW of about 15 KDa to about 40 KDa. Depositingthe second polymer on the medical device may use at least one of a RESScoating process, an eSTAT coating process, a dip coating process, and aspray coating process.

In some embodiments of the methods, coatings, and/or devices providedherein, the intervention site is in or on the body of a subject. In someembodiments, the intervention site is a vascular wall. In someembodiments, the intervention site is a non-vascular lumen wall. In someembodiments, the intervention site is a vascular cavity wall. In someembodiments of the methods and/or devices provided herein, theintervention site is a wall of a body cavity. In some embodiments, thebody cavity is the result of a lumpectomy. In some embodiments, theintervention site is a cannulized site within a subject. In someembodiments of the methods and/or devices provided herein, theintervention site is a sinus wall. In some embodiments, the interventionsite is a sinus cavity wall. In some embodiments, the active agentcomprises a corticosteriod.

In some embodiments of the methods, coatings, and/or devices providedherein, the coating is capable of at least one of: retarding healing,delaying healing, and preventing healing. In some embodiments, thecoating is capable of at least one of: retarding, delaying, andpreventing the inflammatory phase of healing. In some embodiments, thecoating is capable of at least one of: retarding, delaying, andpreventing the proliferative phase of healing. In some embodiments, thecoating is capable of at least one of: retarding, delaying, andpreventing the maturation phase of healing. In some embodiments, thecoating is capable of at least one of: retarding, delaying, andpreventing the remodeling phase of healing. In some embodiments, theactive agent comprises an anti-angiogenic agent.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andtransferring at least a portion of the coating from the substrate to theintervention site upon stimulating the coating with a stimulation.

Other compounds that may be used in lieu of Sirolimus (or in additionthereto) include, for non-limiting example: Sirolimus which has a FKBP12binding (nM) of 0.4-2.3 μM and an Antiproliferative potency (nM) of0.1-3.5 nM; Everolimus which has a FKBP12 binding (nM) of 1.8-2.6 nM andan Antiproliferative potency (nM) of 0.9-3.6 nM; Zotarolimus which has aFKBP12 binding (nM) of 2.0-3.2 nM and an Antiproliferative potency (nM)of 0.2-2.7 nM; Biolimus which has an Antiproliferative potency (nM) ofabout 10 nM; Temsirolimus which has a FKBP12 binding (nM) and anAntiproliferative potency (nM) that is about the same as Sirolimus;Tacrolimus which has a FKBP12 binding (nM) of 0.2-0.4 nM and anAntiproliferative potency (nM) of about 350 nM; Pimecrolimus which has aFKBP12 binding (nM) of about 1.2 nM and an Antiproliferative potency(nM) of about 1 μM.

Alternative compounds that may be used in lieu of sirolimus (or inaddition thereto) include drugs that were not sufficiently potent toeffectively deliver from a drug stent platform may be more effectivewhen delivered from a coated balloon (if the drug is highly lipophilic),for non-limiting example: Dipyradamole, Cerivastatin, Troglitazone,and/or Cilostazol. Dipyradamole may be an appropriate drug for use on acoating of a balloon, for example, since it inhibits VSMC (vascularsmooth muscle cell) proliferation, is anti-inflammatory, improvesendothelial function, and provides local release of t-PA (tissueplasminogen activator). Cerivastatin may be an appropriate drug for useon a coating of a balloon, for example, since it inhibits VSMCproliferation, is anti-inflammatory, improves endothelial function, andcan stabilize vulnerable plaque. Troglitazone may be an appropriate drugfor use on a coating of a balloon, for example, since it inhibits VSMCproliferation, is antiinflammatory, improves endothelial function, andmay provide vascular lipid reduction. Cilostazol may be an appropriatedrug for use on a coating of a balloon, for example, since it inhibitsVSMC proliferation, may be anti-inflammatory, improves endothelialfunction, and is a vasodilator and/or increases NO (nitric oxide)release and/or production of NO.

Other drugs that may be appropriate for use on a drug balloon as acoating that is released thereby include the following: Drugs to preventelastic recoil such as smooth muscle cell relaxants and/or agents thatbind elastin; Drugs to prevent reperfusion injury such as ANP,atorvastatin, erythropoietin, and/or glucagon-like peptide 1; Drugs tostimulate collateral blood flow such as Vasodilators and/or Growthfactors (GF) and GF activators. Drug coated balloons may be useful inlower extremities and in peripheral indications, such as in PTA(Percutaneous transluminal angioplasty) and in combination with a barestent, in situations of in stent restenosis, following atherectomy. Drugcoated balloons may be particularly useful in certain coronaryindications, such as following in stent restenosis, in small vesselangioplasty situations, in bifurcations, and in combination with a baremetal stent. Other uses include in AV Fistulae and Grafts (dialysis), inthe nasal sinus, in neurovascular vessels, in renal vessels orapplications, in anti-cancer applications, and in urologicalapplications, a) Fistulae and Grafts (dialysis) Fistulae and Grafts(dialysis)Fistulae and Grafts (dialysis).

In some embodiments, the device releases at least 3% of the active agentto artery in vivo. In some embodiments, the device releases at least 5%of the active agent to artery in vivo. In some embodiments, the devicereleases at least 10% of the active agent in vivo. In some embodiments,the device releases at least 5% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 7% of the active agent to artery upon inflation of theballoon in vivo. In some embodiments, the device releases at least 10%>of the active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases at least 15%> of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases at least 20% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 25% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least30% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases at least 40% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 50% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases between 2% and 50% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 50% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between5% and 50% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 30% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3% and 25% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3% and 20% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 3% and 15% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 1% and 15% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between1%> and 10%> of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 10%> ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 1% and 5% of the activeagent to artery upon inflation of the balloon in vivo.

As used herein, depending on the embodiment, “upon inflation” means assoon as reasonably possible following removal of the device from thetreatment site. This may include timings such as about 1 minute, about 5minutes from removal of the device from the treatment site, within 1 to15 minutes from the removal of the device from the treatment site,within 1 to 15 minutes from the removal of the device from the treatmentsite, within 1 to 20 minutes from the removal of the device from thetreatment site, within 1 minute to 1 hour from the removal of the devicefrom the treatment site, within 1 minute to 2 hour from the removal ofthe device from the treatment site, and/or within 1 minute to 3 hoursfrom the removal of the device from the treatment site.

Example 5: Delivery of Rapamycin from Coated Invertable Balloons

Provided herein is a device comprising an invertable balloon, a coatingon the abluminal side of the invertable balloon, wherein the coatingcomprises an active agent and a binding agent. In some embodiments, thedevice releases at least 3% of the active agent to artery upon inflationof the balloon in vivo.

In some embodiments, the device releases at least 5% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases at least 7% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 10%) of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least15% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases at least 20%> of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 25% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases at least 30%1> of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 40%) of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least50%> of the active agent to artery upon inflation of the balloon invivo. In some embodiments, the device releases between 2% and 50%> ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3% and 50% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 5% and 50%> of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 3% and 30%> of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 25% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between3% and 20% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 15% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 1%> and 15%> of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1%> and 10%> of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3% and 10%) of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 1%> and 5% of the active agent to arteryupon inflation of the balloon in vivo.

Example invertable balloons (which may also and/or alternatively becalled evertable balloons) include, but are not limited to, thosedescribed in U.S. Pat. No. 6,039,721 filed Dec. 3, 1997; and U.S. Pat.No. 4,606,347 filed Aug. 8, 1985 which patents are incorporated hereinby reference in their entirety. In some embodiments the abluminalsurface of the balloon is coated prior to inversion, and once coated,the balloon is inverted such that the abluminal surface of the balloonis protected from either blood flow during tracking or tracking contactwith the vessel wall, or both, until the balloon catheter is positionednear the treatment site, usually just proximally to the site. As usedherein, “abluminal side” or “abluminal surface” refers to a portion ofthe balloon having coating thereon, and intended to deliver the coating(agent) to the treatment site or location—i.e. the lumen of the vesselin the case of a treatment site that is a vessel. The balloon is thenun-inverted such that the abluminal surface is positioned within thetreatment site.

In an embodiment wherein the balloon is inverted within a catheter, itmay be pushed out of the catheter using either pressure from theindeflator or another form of un-inversion of the balloon, such as fornonlimiting example, by moving the distal end of the balloon distallythrough the balloon itself, essentially unrolling the balloon into thetreatment site such that the coated portion of the balloon is adjacentthe treatment site. In certain embodiments where the balloon in invertedon the outside of the catheter, a similar movement and/or pressure fromthe indeflator can move the distal end of the balloon distally therebyunrolling the coated side of the balloon into proximity of the treatmentsite. In some embodiments, the balloon may be partially un-inverted,such that the treatment length may be controlled. The balloon thereafteris inflated such that the abluminal surface that is coated contactsand/or dilates the treatment site, thereby delivering the coating or aportion thereof to the treatment site.

Any of the devices, coatings, and/or methods described herein may becombined with an inverteable type of balloon to deliver the coating in amanner that reduces and/or substantially eliminates loss of coating dueto tracking and/or blood flow and/or other in-transit coating loss priorto locating the device at the treatment site (i.e. delivering the deviceto the treatment site). In some embodiments, at most 1%> of coating isremoved from the balloon due to tracking of the coated balloon to thetreatment site. In some embodiments, at most 3%> of coating is removedfrom the balloon due to tracking of the coated balloon to the treatmentsite. In some embodiments, at most 5% of coating is removed from theballoon due to tracking of the coated balloon to the treatment site. Insome embodiments, at most 10% of coating is removed from the balloon dueto tracking of the coated balloon to the treatment site. In someembodiments, at most 15%> of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 20%> of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 25% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 30% of coating is removed from the balloon due totracking of the coated balloon to the treatment site.

As used herein, depending on the embodiment, “upon inflation” means assoon as reasonably possible following removal of the device from thetreatment site. This may include timings such as about 1 minute, about 5minutes from removal of the device from the treatment site, within 1 to15 minutes from the removal of the device from the treatment site,within 1 to 15 minutes from the removal of the device from the treatmentsite, within 1 to 20 minutes from the removal of the device from thetreatment site, within 1 minute to 1 hour from the removal of the devicefrom the treatment site, within 1 minute to 2 hour from the removal ofthe device from the treatment site, and/or within 1 minute to 3 hoursfrom the removal of the device from the treatment site.

Example 6: Delivery of Rapamycin from Sheathed Coated Balloons

Provided herein is a device comprising an balloon, a coating on the abluminal side of the balloon, and a sheath over the balloon, wherein thecoating comprises an active agent and a binding agent. In someembodiments, the device releases at least 3% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thesheath may be retracted. In some embodiments, the sheath may beretracted to expose the coating to the treatment site. In someembodiments, the sheath covers the coated balloon until the balloonreaches the treatment site. In some embodiments the sheath may beretracted once the coated balloon is positioned near and/or at thetreatment site. In some embodiments, the sheath covers the coatedballoon until the balloon is proximal to the treatment site. In someembodiments, the sheath covers the coated balloon until the balloon isdistal to the treatment site. In some embodiments, the sheath covers thecoated balloon until the balloon is within to the treatment site. Insome embodiments, the sheath may be moved over the balloon followingdeflation of the balloon after the coating (or a portion thereof) hasbeen released to the artery, and the catheter may be removed such thatthe coated balloon is covered during removal from the subject. In someembodiments, the sheath may remain in a retracted state followingdeflation of the balloon after the coating (or a portion thereof) hasbeen released to the artery, and the catheter may be removed such thatthe coated balloon is exposed to the delivery track during removal fromthe subject.

Any of the devices, coatings, and/or methods described herein may becombined with a sheath to deliver the coating in a manner that reducesand/or substantially eliminates loss of coating due to tracking and/orblood flow and/or other in-transit coating loss prior to locating thedevice at the treatment site (i.e. delivering the device to thetreatment site). In some embodiments, at most 1% of coating is removedfrom the balloon due to tracking of the coated balloon to the treatmentsite. In some embodiments, at most 3% of coating is removed from theballoon due to tracking of the coated balloon to the treatment site. Insome embodiments, at most 5% of coating is removed from the balloon dueto tracking of the coated balloon to the treatment site. In someembodiments, at most 10% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 15%> of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 20%> of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 25% of coating is removed from the balloon due totracking of the coated balloon to the treatment site. In someembodiments, at most 30% of coating is removed from the balloon due totracking of the coated balloon to the treatment site.

In some embodiments, the device releases at least 5% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases at least 7% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 10%) of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least15% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases at least 20% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 25% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases at least 30% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 40%) of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least50% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases between 2% and 50% of theactive agent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3% and 50% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 5% and 50%) of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 30% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between3% and 25% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 20% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3% and 15% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1% and 15% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 1% and 10% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 10% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between1% and 5% of the active agent to artery upon inflation of the balloon invivo.

As used herein, depending on the embodiment, “upon inflation” means assoon as reasonably possible following removal of the device from thetreatment site. This may include timings such as about 1 minute, about 5minutes from removal of the device from the treatment site, within 1 to15 minutes from the removal of the device from the treatment site,within 1 to 15 minutes from the removal of the device from the treatmentsite, within 1 to 20 minutes from the removal of the device from thetreatment site, within 1 minute to 1 hour from the removal of the devicefrom the treatment site, within 1 minute to 2 hour from the removal ofthe device from the treatment site, and/or within 1 minute to 3 hoursfrom the removal of the device from the treatment site.

Example 7: Delivery of Rapamycin from Coated Balloons with Occluder

Provided herein is a device comprising a balloon, a coating on theballoon, and an occluder, wherein the coating comprises an active agentand a binding agent. In some embodiments, the occluder is a flowoccluder configured to block the flow of bodily fluids (e.g. blood) atthe treatment site during exposure of the coating to the treatment site.In some embodiments, the device releases at least 3% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the occluder comprises a second balloon that occludes the flow of theblood at the treatment site. In some embodiments, the balloon comprisesthe occluder, such that the balloon has two sections the flow occluderand the coated portion, wherein the flow occluder occludes the flow ofthe blood at the treatment site. In some embodiments, the balloon isdual-noded, wherein the distal node is coated and wherein the proximalnode is the occluder. In some embodiments, the occluder is locatedproximally from the balloon, and/or portion thereof, having coatingthereon. In some embodiments, the balloon is dual-noded, wherein theproximal node is coated and wherein the distal node is the occluder. Insome embodiments the occluder is located distally from the balloon,and/or portion thereof, having coating thereon. In some embodiments, theballoon is a shape appropriate for the treatment site, such that theoccluder portion of the balloon is the appropriate shape to occlude flowof blood at the treatment site. In some embodiments, the occludersubstantially conforms to the shape of a treatment area near thetreatment site such blood flow at the treatment site is occludedthereby. In some embodiments, the balloon is only partially coated, suchthat either or both the distal and proximal end of the balloon is notcoated, and the distal and/or proximal end of the balloon is theoccluder.

Provided herein is a device comprising a first balloon, a coating on thefirst balloon, and a second balloon capable of occluding flow of bloodat the treatment site during expansion of the first balloon at thetreatment site. In some embodiments, the occluder is a second balloonwhich is not the balloon having coating thereon. In some embodiments,the occluder is located proximally from the balloon, and/or portionthereof, having coating thereon. In some embodiments the occluder islocated distally from the balloon, and/or portion thereof, havingcoating thereon.

Provided herein is a device comprising a first balloon, a coating on thefirst balloon, and a second balloon configured such that the secondballoon expands prior to expansion of the first balloon. In someembodiments the occluder occludes the flow of the blood at the treatmentprior to expansion of the portion of the balloon. In some embodiments,the occluder is located proximally from the balloon, and/or portionthereof, having coating thereon. In some embodiments the occluder islocated distally from the balloon, and/or portion thereof, havingcoating thereon.

In some embodiments, the occluder is not a balloon, but is another formof occluder that is configured to occlude flow of blood at the treatmentsite. In some embodiments, the occluder is deployable and retractable,such that it can be deployed prior to inflation of the balloon havingcoating thereon, and following balloon inflation and delivery of theagent to the treatment site, the occluder can be retracted and removedeither with the removal of the balloon, or following removal of theballoon from the treatment site.

In some embodiments, the occluder has a second coating thereon, having asecond agent and/or polymer coated thereon as described elsewhereherein, according to any of the methods and processes as noted herein.The second coating in some embodiments comprises a binding agent. Thesecond coating in some embodiments does not comprise a binding agent.

In some embodiments, the device releases at least 5% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases at least 7% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 10% of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least15%> of the active agent to artery upon inflation of the balloon invivo. In some embodiments, the device releases at least 20%> of theactive agent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases at least 25% of the active agent toartery upon inflation of the balloon in vivo. In some embodiments, thedevice releases at least 30% of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases at least 40%) of the active agent to artery upon inflation ofthe balloon in vivo. In some embodiments, the device releases at least50% of the active agent to artery upon inflation of the balloon in vivo.In some embodiments, the device releases between 2% and 50% of theactive agent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 3% and 50% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 5% and 50%) of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 30% of the active agent to artery upon inflationof the balloon in vivo. In some embodiments, the device releases between3% and 25% of the active agent to artery upon inflation of the balloonin vivo. In some embodiments, the device releases between 3% and 20% ofthe active agent to artery upon inflation of the balloon in vivo. Insome embodiments, the device releases between 3% and 15% of the activeagent to artery upon inflation of the balloon in vivo. In someembodiments, the device releases between 1% and 15% of the active agentto artery upon inflation of the balloon in vivo. In some embodiments,the device releases between 1% and 10% of the active agent to arteryupon inflation of the balloon in vivo. In some embodiments, the devicereleases between 3% and 10%) of the active agent to artery uponinflation of the balloon in vivo. In some embodiments, the devicereleases between 1%> and 5%> of the active agent to artery uponinflation of the balloon in vivo.

Much of the description herein is provided with reference to a balloonand a treatment site that is a artery for ease of description andbrevity. Nevertheless, the methods, descriptions, devices, and coatingsdescribed herein apply to alternative devices and treatment locations.

Unless otherwise stated, use of the term “about” in this description canmean variations of 0.1%, 0.5%, 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%,40%, and/or 50%, depending on the particular embodiment. Where theelement being described is itself expressed as a percent, the variationsare not meant to be percents of percents, rather they are variations asan absolute percent—i.e. an element that is expressed as “about 5%” maybe actually 5%+/−1%, or from 4% to 6%, depending on the embodiment. Onlythe variations that would be rational to one of ordinary skill in theart are contemplated herein. For example, where the element itself isexpressed as a small percent, and a person of ordinary skill would knowthat the element is not rational to go below 0, the variationscontemplated would not go below zero (i.e. about 5% could mean 5%+1-5%or 0-10%, but not 5%+/−10%) or −5%) to 15%), where this is notreasonable to one of skill in the art for the element being described).

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. While embodiments of the presentinvention have been indicated and described herein, it will be obviousto those skilled in the art that such embodiments are provided by way ofexample only. Numerous variations, changes, and substitutions will nowoccur to those skilled in the art without departing from the invention.It should be understood that various alternatives to the embodiments ofthe invention described herein may be employed in practicing theinvention. It is intended that the following claims define the scope ofthe invention and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

1. A method comprising the steps of: providing a device comprising aballoon; and a coating on at least a portion of the balloon, wherein thecoating comprises an active agent, a polymer and a cationic bindingagent, wherein the active agent includes a plurality of macrolideimmunosuppressive drug particles in crystalline form, some of theparticles having a portion uncovered by the polymer and some of theparticles being fully encapsulated in the polymer; inflating the balloonof the device in vivo; and transferring at least 3% of the active agentand at least a portion of the polymer to a treatment site upon expansionof the balloon in vivo, wherein the binding agent comprises at least oneof: Polyarginine, Polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethylcellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI(Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB(Dimethylditetradecylammonium bromide).